Group 1—Carcinogenic to Humans (74)

Agents and groups of agents

Aflatoxins [1402-68-2] (1993)

4-Aminobiphenyl [92-67-1]

Arsenic [7440-38-2] and arsenic compounds²

Asbestos [1332-21-4]

Azathioprine [446-86-6]

Benzene [71-43-2]

Benzidine [92-87-5]

Beryllium [7440-41-7] and beryllium compounds (1993)³

Bis(2-chloroethyl)-2-naphthylamine (Chlornaphazine)[494-03-1]

Bis(chloromethyl)ether [542-88-1] and chloromethyl methyl ether [107-30-2] (technical-grade)

1,4-Butanediol dimethanesulphonate (Myleran) [55-98-1]

Cadmium [7440-43-9] and cadmium compounds (1993)³

Chlorambucil [305-03-3]

1-(2-Chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (Methyl-CCNU; Semustine) [13909-09-6]

Chromium[VI] compounds (1990)³

Ciclosporin [79217-60-0] (1990)

Cyclophosphamide [50-18-0] [6055-19-2]

Diethylstilboestrol [56-53-1]

Erionite [66733-21-9]

Ethylene oxide⁴ [75-21-8] (1994)

Helicobacter pylori (infection with) (1994)

Hepatitis B virus (chronic infection with) (1993)

Hepatitis C virus (chronic infection with) (1993)

Human papillomavirus type 16 (1995)

Human papillomavirus type 18 (1995)

Human T-cell lymphotropic virus type I (1996)

Melphalan [148-82-3]

8-Methoxypsoralen (Methoxsalen) [298-81-7] plus ultraviolet A radiation

MOPP and other combined chemotherapy including alkylating agents

Mustard gas (Sulphur mustard) [505-60-2]

2-Naphthylamine [91-59-8]

Nickel compounds (1990)³

Oestrogen replacement therapy

Oestrogens, nonsteroidal²

Oestrogens, steroidal²

Opisthorchis viverrini (infection with) (1994)

Oral contraceptives, combined⁵

Oral contraceptives, sequential

Radon [10043-92-2] and its decay products (1988)

Schistosoma haematobium (infection with) (1994)

Silica [14808-60-7] crystalline (inhaled in the form of quartz or cristobalite from occupational sources)

Solar radiation (1992)

Talc containing asbestiform fibres

Tamoxifen [10540-29-1]⁶

Thiotepa [52-24-4] (1990)

Treosulphan [299-75-2]

Vinyl chloride [75-01-4]

Mixtures

Alcoholic beverages (1988)

Analgesic mixtures containing phenacetin

Betel quid with tobacco

Coal-tar pitches [65996-93-2]

Coal-tars [8007-45-2]

Mineral oils, untreated and mildly treated

Salted fish (Chinese-style) (1993)

Shale oils [68308-34-9]

Soots

Tobacco products, smokeless

Tobacco smoke

Wood dust

Exposure circumstances

Aluminium production

Auramine, manufacture of

Boot and shoe manufacture and repair

Coal gasification

Coke production

Furniture and cabinet making

Haematite mining (underground) with exposure to radon

Iron and steel founding

Isopropanol manufacture (strong-acid process)

Magenta, manufacture of (1993)

Painter (occupational exposure as a) (1989)

Rubber industry

Strong-inorganic-acid mists containing sulphuric acid (occupational exposure to) (1992)

Group 2A—Probably carcinogenic to humans (56)

Agents and groups of agents

Acrylamide [79-06-1] (1994)⁸

Acrylonitrile [107-13-1]

Adriamycin⁸ [23214-92-8]

Androgenic (anabolic) steroids

Azacitidine⁸ [320-67-2] (1990)

Benz[a]anthracene⁸ [56-55-3]

Benzidine-based dyes⁸

Benzo[a]pyrene⁸ [50-32-8]

Bischloroethyl nitrosourea (BCNU) [154-93-8]

1,3-Butadiene [106-99-0] (1992)

Captafol [2425-06-1] (1991)

Chloramphenicol [56-75-7] (1990)

1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea⁸ (CCNU)[13010-47-4]

p-Chloro-o-toluidine [95-69-2] and its strong acid salts (1990)³

Chlorozotocin⁸ [54749-90-5] (1990)

Cisplatin⁸ [15663-27-1]

Clonorchis sinensis (infection with)⁸ (1994)

Dibenz[a,h]anthracene⁸ [53-70-3]

Diethyl sulphate [64-67-5] (1992)

Dimethylcarbamoyl chloride⁸ [79-44-7]

Dimethyl sulphate⁸ [77-78-1]

Epichlorohydrin⁸ [106-89-8]

Ethylene dibromide⁸ [106-93-4]

N-Ethyl-N-nitrosourea⁸ [759-73-9]

Formaldehyde [50-00-0])

IQ⁸ (2-Amino-3-methylimidazo[4,5-f]quinoline) [76180-96-6] (1993)

5-Methoxypsoralen⁸ [484-20-8]

4,4´-Methylene bis(2-chloroaniline) (MOCA)⁸ [101-14-4] (1993)

N-Methyl-N´-nitro-N-nitrosoguanidine⁸ (MNNG) [70-25-7]

N-Methyl-N-nitrosourea⁸ [684-93-5]

Nitrogen mustard [51-75-2]

N-Nitrosodiethylamine⁸ [55-18-5]

N-Nitrosodimethylamine ⁸ [62-75-9]

Phenacetin [62-44-2]

Procarbazine hydrochloride⁸ [366-70-1]

Tetrachloroethylene [127-18-4]

Trichloroethylene [79-01-6]

Styrene-7,8-oxide⁸ [96-09-3] (1994)

Tris(2,3-dibromopropyl)phosphate⁸ [126-72-7]

Ultraviolet radiation A⁸ (1992)

Ultraviolet radiation B⁸ (1992)

Ultraviolet radiation C⁸ (1992)

Vinyl bromide6 [593-60-2]

Vinyl fluoride [75-02-5]

Mixtures

Creosotes [8001-58-9]

Diesel engine exhaust (1989)

Hot mate (1991)

Non-arsenical insecticides (occupational exposures in spraying and application of) (1991)

Polychlorinated biphenyls [1336-36-3]

Exposure circumstances

Art glass, glass containers and pressed ware (manufacture of) (1993)

Hairdresser or barber (occupational exposure as a) (1993)

Petroleum refining (occupational exposures in) (1989)

Sunlamps and sunbeds (use of) (1992)

Group 2B—Possibly carcinogenic to humans (225)

Agents and groups of agents

A–α–C (2-Amino-9H-pyrido[2,3-b]indole) [26148-68-5]

Acetaldehyde [75-07-0]

Acetamide [60-35-5]

AF-2 [2-(2-Furyl)-3-(5-nitro-2-furyl)acrylamide] [3688-53-7]

Aflatoxin M1 [6795-23-9] (1993)

p-Aminoazobenzene [60-09-3]

o-Aminoazotoluene [97-56-3]

2-Amino-5-(5-nitro-2-furyl)-1,3,4-thiadiazole [712-68-5]

Amitrole [61-82-5]

o-Anisidine [90-04-0]

Antimony trioxide [1309-64-4] (1989)

Aramite [140-57-8]

Atrazine⁹ [1912-24-9] (1991)

Auramine [492-80-8] (technical-grade)

Azaserine [115-02-6]

Benzo[b]fluoranthene [205-99-2]

Benzo[j]fluoranthene [205-82-3]

Benzo[k]fluoranthene [207-08-9]

Benzyl violet 4B [1694-09-3]

Bleomycins [11056-06-7]

Bracken fern

Bromodichloromethane [75-27-4] (1991)

Butylated hydroxyanisole (BHA) [25013-16-5]

β-Butyrolactone [3068-88-0]

Caffeic acid [331-39-5] (1993)

Carbon-black extracts

Carbon tetrachloride [56-23-5]

Ceramic fibres

Chlordane [57-74-9] (1991)

Chlordecone (Kepone) [143-50-0]

Chlorendic acid [115-28-6] (1990)

α-Chlorinated toluenes (benzyl chloride, benzal chloride,benzotrichloride)

p-Chloroaniline [106-47-8] (1993)

Chloroform [67-66-3]

1-Chloro-2-methylpropene [513-37-1]

Chlorophenols

Chlorophenoxy herbicides

4-Chloro-o-phenylenediamine [95-83-0]

CI Acid Red 114 [6459-94-5] (1993)

CI Basic Red 9 [569-61-9] (1993)

CI Direct Blue 15 [2429-74-5] (1993)

Citrus Red No. 2 [6358-53-8]

Cobalt [7440-48-4] and cobalt compounds³ (1991)

p-Cresidine [120-71-8]

Cycasin [14901-08-7]

Dacarbazine [4342-03-4]

Dantron (Chrysazin; 1,8-Dihydroxyanthraquinone) [117-10-2] (1990)

Daunomycin [20830-81-3]

DDT´-DDT, 50-29-3] (1991)

N,N´-Diacetylbenzidine [613-35-4]

2,4-Diaminoanisole [615-05-4]

4,4´-Diaminodiphenyl ether [101-80-4]

2,4-Diaminotoluene [95-80-7]

Dibenz[a,h]acridine [226-36-8]

Dibenz[a,j]acridine [224-42-0]

7H-Dibenzo[c,g]carbazole [194-59-2]

Dibenzo[a,e]pyrene [192-65-4]

Dibenzo[a,h]pyrene [189-64-0]

Dibenzo[a,i]pyrene [189-55-9]

Dibenzo[a,l]pyrene [191-30-0]

1,2-Dibromo-3-chloropropane [96-12-8]

p-Dichlorobenzene [106-46-7]

3,3´-Dichlorobenzidine [91-94-1]

3,3´-Dichloro-4,4´-diaminodiphenyl ether [28434-86-8]

1,2-Dichloroethane [107-06-2]

Dichloromethane (methylene chloride) [75-09-2]

1,3-Dichloropropene [542-75-6] (technical grade)

Dichlorvos [62-73-7] (1991)

Diepoxybutane [1464-53-5]

Di(2-ethylhexyl)phthalate [117-81-7]

1,2-Diethylhydrazine [1615-80-1]

Diglycidyl resorcinol ether [101-90-6]

Dihydrosafrole [94-58-6]

Diisopropyl sulphate [2973-10-6] (1992)

3,3´-Dimethoxybenzidine (o-Dianisidine) [119-90-4]

p-Dimethylaminoazobenzene [60-11-7]

trans-2-[(Dimethylamino)methylimino]-5-[2-(5-nitro-2-furyl)-vinyl]-1,3,4-oxadiazole [25962-77-0]

2,6-Dimethylaniline (2,6-xylidine) [87-62-7] (1993)

3,3´-Dimethylbenzidine (o-tolidine) [119-93-7]

Dimethylformamide [68-12-2] (1989)

1,1-Dimethylhydrazine [57-14-7]

1,2-Dimethylhydrazine [540-73-8]

3,7-Dinitrofluoranthene [105735-71-5]

3,9-Dinitrofluoranthene [22506-53-2]

1,6-Dinitropyrene [42397-64-8] (1989)

1,8-Dinitropyrene [42397-65-9] (1989)

2,4-Dinitrotoluene [121-14-2]

2,6-Dinitrotoluene [606-20-2]

1,4-Dioxane [123-91-1]

Disperse Blue 1 [2475-45-8] (1990)

Ethyl acrylate [140-88-5]

Ethylene thiourea [96-45-7]

Ethyl methanesulphonate [62-50-0]

2-(2-Formylhydrazino)-4-(5-nitro-2-furyl)thiazole [3570-75-0]

Glass wool (1988)

Glu-P-1 (2-amino-6-methyldipyrido[1,2-a:3´,2´-d]imidazole)[67730-11-4]

Glu-P-2 (2-aminodipyrido[1,2-a:3´,2´-d]imidazole) [67730-10-3]

Glycidaldehyde [765-34-4]

Griseofulvin [126-07-8]

HC Blue No. 1 [2784-94-3] (1993)

Heptachlor [76-44-8] (1991)

Hexachlorobenzene [118-74-1]

Hexachlorocyclohexanes

Hexamethylphosphoramide [680-31-9]

Human immunodeficiency virus type 2 (infection with) (1996)

Human papillomaviruses: some types other than 16, 18, 31 and 33 (1995)

Hydrazine [302-01-2]

Indeno[1,2,3-cd]pyrene [193-39-5]

Iron-dextran complex [9004-66-4]

Isoprene [78-79-5] (1994)

Lasiocarpine [303-34-4]

Lead [7439-92-1] and lead compounds, inorganic³

Magenta [632-99-5] (containing CI Basic Red 9) (1993)

MeA-α-C (2-Amino-3-methyl-9H-pyrido[2,3-b]indole)[68006-83-7]

Medroxyprogesterone acetate [71-58-9]

MeIQ (2-Amino-3,4-dimethylimidazo[4,5-f]quinoline)[77094-11-2] (1993)

MeIQx (2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline) [77500-04-0] (1993)

Merphalan [531-76-0]

2-Methylaziridine (propyleneimine) [75-55-8]

Methylazoxymethanol acetate [592-62-1]

5-Methylchrysene [3697-24-3]

4,4´-Methylene bis(2-methylaniline) [838-88-0]

4,4´-Methylenedianiline [101-77-9]

Methylmercury compounds (1993)³

Methyl methanesulphonate [66-27-3]

2-Methyl-1-nitroanthraquinone [129-15-7] (uncertain purity)

N-Methyl-N-nitrosourethane [615-53-2]

Methylthiouracil [56-04-2]

Metronidazole [443-48-1]

Mirex [2385-85-5]

Mitomycin C [50-07-7]

Monocrotaline [315-22-0]

5-(Morpholinomethyl)-3-[(5-nitrofurfurylidene)amino]-2-oxazolidinone [3795-88-8]

Nafenopin [3771-19-5]

Nickel, metallic [7440-02-0] (1990)

Niridazole [61-57-4]

Nitrilotriacetic acid [139-13-9] and its salts (1990)³

5-Nitroacenaphthene [602-87-9]

2-Nitroanisole [91-23-6] (1996)

Nitrobenzene [98-95-3] (1996)

6-Nitrochrysene [7496-02-8] (1989)

Nitrofen [1836-75-5], technical-grade

2-Nitrofluorene [607-57-8] (1989)

1-[(5-Nitrofurfurylidene)amino]-2-imidazolidinone [555-84-0]

N-[4-(5-Nitro-2-furyl)-2-thiazolyl]acetamide [531-82-8]

Nitrogen mustard N-oxide [126-85-2]

2-Nitropropane [79-46-9]

1-Nitropyrene [5522-43-0] (1989)

4-Nitropyrene [57835-92-4] (1989)

N-Nitrosodi-n-butylamine [924-16-3]

N-Nitrosodiethanolamine [1116-54-7]

N-Nitrosodi-n-propylamine [621-64-7]

3-(N-Nitrosomethylamino)propionitrile [60153-49-3]

4-(N-Nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) [64091-91-4]

N-Nitrosomethylethylamine [10595-95-6]

N-Nitrosomethylvinylamine [4549-40-0]

N-Nitrosomorpholine [59-89-2]

N‘-Nitrosonornicotine [16543-55-8]

N-Nitrosopiperidine [100-75-4]

N-Nitrosopyrrolidine [930-55-2]

N-Nitrososarcosine [13256-22-9]

Ochratoxin A [303-47-9] (1993)

Oil Orange SS [2646-17-5]

Oxazepam [604-75-1] (1996)

Palygorskite (attapulgite) [12174-11-7] (long fibres, >>5 micro-meters) (1997)

Panfuran S (containing dihydroxymethylfuratrizine [794-93-4])

Pentachlorophenol [87-86-5] (1991)

Phenazopyridine hydrochloride [136-40-3]

Phenobarbital [50-06-6]

Phenoxybenzamine hydrochloride [63-92-3]

Phenyl glycidyl ether [122-60-1] (1989)

Phenytoin [57-41-0]

PhIP (2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) [105650-23-5] (1993)

Ponceau MX [3761-53-3]

Ponceau 3R [3564-09-8]

Potassium bromate [7758-01-2]

Progestins

1,3-Propane sultone [1120-71-4]

β-Propiolactone [57-57-8]

Propylene oxide [75-56-9] (1994)

Propylthiouracil [51-52-5]

Rockwool (1988)

Saccharin [81-07-2]

Safrole [94-59-7]

Schistosoma japonicum (infection with) (1994)

Slagwool (1988)

Sodium o-phenylphenate [132-27-4]

Sterigmatocystin [10048-13-2]

Streptozotocin [18883-66-4]

Styrene [100-42-5] (1994)

Sulfallate [95-06-7]

Tetranitromethane [509-14-8] (1996)

Thioacetamide [62-55-5]

4,4´-Thiodianiline [139-65-1]

Thiourea [62-56-6]

Toluene diisocyanates [26471-62-5]

o-Toluidine [95-53-4]

Trichlormethine (Trimustine hydrochloride) [817-09-4] (1990)

Trp-P-1 (3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole) [62450-06-0]

Trp-P-2 (3-Amino-1-methyl-5H-pyrido[4,3-b]indole) [62450-07-1]

Trypan blue [72-57-1]

Uracil mustard [66-75-1]

Urethane [51-79-6]

Vinyl acetate [108-05-4] (1995)

4-Vinylcyclohexene [100-40-3] (1994)

4-Vinylcyclohexene diepoxide [107-87-6] (1994)

Mixtures

Bitumens [8052-42-4], extracts of steam-refined and air-refined

Carrageenan [9000-07-1], degraded

Chlorinated paraffins of average carbon chain length C12 and average degree of chlorination approximately 60% (1990)

Coffee (urinary bladder)⁹ (1991)

Diesel fuel, marine (1989)

Engine exhaust, gasoline (1989)

Fuel oils, residual (heavy) (1989)

Gasoline (1989)

Pickled vegetables (traditional in Asia) (1993)

Polybrominated biphenyls [Firemaster BP-6, 59536-65-1]

Toxaphene (Polychlorinated camphenes) [8001-35-2]

Toxins derived from Fusarium moniliforme (1993)

Welding fumes (1990)

Exposure circumstances

Carpentry and joinery

Dry cleaning (occupational exposures in) (1995)

Printing processes (occupational exposures in) (1996)

Textile manufacturing industry (work in) (1990)

Group 3—Unclassifiable as to carcinogenicity to humans (480)

Agents and groups of agents

Acridine orange [494-38-2]

Acriflavinium chloride [8018-07-3]

Acrolein [107-02-8]

Acrylic acid [79-10-7]

Acrylic fibres

Acrylonitrile-butadiene-styrene copolymers

Actinomycin D [50-76-0]

Aldicarb [116-06-3] (1991)

Aldrin [309-00-2]

Allyl chloride [107-05-1]

Allyl isothiocyanate [57-06-7]

Allyl isovalerate [2835-39-4]

Amaranth [915-67-3]

5-Aminoacenaphthene [4657-93-6]

2-Aminoanthraquinone [117-79-3]

p-Aminobenzoic acid [150-13-0]

1-Amino-2-methylanthraquinone [82-28-0]

2-Amino-4-nitrophenol [99-57-0] (1993)

2-Amino-5-nitrophenol [121-88-0] (1993)

4-Amino-2-nitrophenol [119-34-6]

2-Amino-5-nitrothiazole [121-66-4]

11-Aminoundecanoic acid [2432-99-7]

Ampicillin [69-53-4] (1990)

Anaesthetics, volatile

Angelicin [523-50-2] plus ultraviolet A radiation

Aniline [62-53-3]

p-Anisidine [104-94-9]

Anthanthrene [191-26-4]

Anthracene [120-12-7]

Anthranilic acid [118-92-3]

Antimony trisulphide [1345-04-6] (1989)

Apholate [52-46-0]

p-Aramid fibrils [24938-64-5] (1997)

Aurothioglucose [12192-57-3]

Aziridine [151-56-4]

2-(1-Aziridinyl)ethanol [1072-52-2]

Aziridyl benzoquinone [800-24-8]

Azobenzene [103-33-3]

Benz[a]acridine [225-11-6]

Benz[c]acridine [225-51-4]

Benzo[ghi]fluoranthene [203-12-3]

Benzo[a]fluorene [238-84-6]

Benzo[b]fluorene [243-17-4]

Benzo[c]fluorene [205-12-9]

Benzo[ghi]perylene [191-24-2]

Benzo[c]phenanthrene [195-19-7]

Benzo[e]pyrene [192-97-2]

p-Benzoquinone dioxime [105-11-3]

Benzoyl chloride [98-88-4]

Benzoyl peroxide [94-36-0]

Benzyl acetate [140-11-4]

Bis(1-aziridinyl)morpholinophosphine sulphide [2168-68-5]

Bis(2-chloroethyl)ether [111-44-4]

1,2-Bis(chloromethoxy)ethane [13483-18-6]

1,4-Bis(chloromethoxymethyl)benzene [56894-91-8]

Bis(2-chloro-1-methylethyl)ether [108-60-1]

Bis(2,3-epoxycyclopentyl)ether [2386-90-5] (1989)

Bisphenol A diglycidyl ether [1675-54-3] (1989)

Bisulphites (1992)

Blue VRS [129-17-9]

Brilliant Blue FCF, disodium salt [3844-45-9]

Bromochloroacetonitrile [83463-62-1] (1991)

Bromoethane [74-96-4] (1991)

Bromoform [75-25-2] (1991)

n-Butyl acrylate [141-32-2]

Butylated hydroxytoluene (BHT) [128-37-0]

Butyl benzyl phthalate [85-68-7]

γ-Butyrolactone [96-48-0]

Caffeine [58-08-2] (1991)

Cantharidin [56-25-7]

Captan [133-06-2]

Carbaryl [63-25-2]

Carbazole [86-74-8]

3-Carbethoxypsoralen [20073-24-9]

Carmoisine [3567-69-9]

Carrageenan [9000-07-1], native

Catechol [120-80-9]

Chloral [75-87-6] (1995)

Chloral hydrate [302-17-0] (1995)

Chlordimeform [6164-98-3]

Chlorinated dibenzodioxins (other than TCDD)

Chlorinated drinking-water (1991)

Chloroacetonitrile [107-14-2] (1991)

Chlorobenzilate [510-15-6]

Chlorodibromomethane [124-48-1] (1991)

Chlorodifluoromethane [75-45-6]

Chloroethane [75-00-3] (1991)

Chlorofluoromethane [593-70-4]

3-Chloro-2-methylpropene [563-47-3] (1995)

4-Chloro-m-phenylenediamine [5131-60-2]

Chloronitrobenzenes [88-73-3; 121-73-3; 100-00-5] (1996)

Chloroprene [126-99-8]

Chloropropham [101-21-3]

Chloroquine [54-05-7]

Chlorothalonil [1897-45-6]

2-Chloro-1,1,1-trifluoroethane [75-88-7]

Cholesterol [57-88-5]

Chromium[III] compounds (1990)

Chromium [7440-47-3], metallic (1990)

Chrysene [218-01-9]

Chrysoidine [532-82-1]

CI Acid Orange 3 [6373-74-6] (1993)

Cimetidine [51481-61-9] (1990)

Cinnamyl anthranilate [87-29-6]

CI Pigment Red 3 [2425-85-6] (1993)

Citrinin [518-75-2]

Clofibrate [637-07-0]

Clomiphene citrate [50-41-9]

Coal dust (1997)

Copper 8-hydroxyquinoline [10380-28-6]

Coronene [191-07-1]

Coumarin [91-64-5]

m-Cresidine [102-50-1]

Crotonaldehyde [4170-30-3] (1995)

Cyclamates [sodium cyclamate, 139-05-9]

Cyclochlorotine [12663-46-6]

Cyclohexanone [108-94-1] (1989)

Cyclopenta[cd]pyrene [27208-37-3]

D & C Red No. 9 [5160-02-1] (1993)

Dapsone [80-08-0]

Decabromodiphenyl oxide [1163-19-5] (1990)

Deltamethrin [52918-63-5] (1991)

Diacetylaminoazotoluene [83-63-6]

Diallate [2303-16-4]

1,2-Diamino-4-nitrobenzene [99-56-9]

1,4-Diamino-2-nitrobenzene [5307-14-2] (1993)

2,5-Diaminotoluene [95-70-5]

Diazepam [439-14-5]

Diazomethane [334-88-3]

Dibenz[a,c]anthracene [215-58-7]

Dibenz[a,j]anthracene [224-41-9]

Dibenzo-p-dioxin (1997)

Dibenzo[a,e]fluoranthene [5385-75-1]

Dibenzo[h,rst]pentaphene [192-47-2]

Dibromoacetonitrile [3252-43-5] (1991)

Dichloroacetic acid [79-43-6] (1995)

Dichloroacetonitrile [3018-12-0] (1991)

Dichloroacetylene [7572-29-4]

o-Dichlorobenzene [95-50-1]

trans-1,4-Dichlorobutene [110-57-6]

2,6-Dichloro-para-phenylenediamine [609-20-1]

1,2-Dichloropropane [78-87-5]

Dicofol [115-32-2]

Dieldrin [60-57-1]

Di(2-ethylhexyl)adipate [103-23-1]

Dihydroxymethylfuratrizine [794-93-4]

Dimethoxane [828-00-2]

3,3´-Dimethoxybenzidine-4,4´-diisocyanate [91-93-0]

p-Dimethylaminoazobenzenediazo sodium sulphonate[140-56-7]

4,4´-Dimethylangelicin [22975-76-4] plus ultraviolet Aradiation

4,5´-Dimethylangelicin [4063-41-6] plus ultraviolet A

N,N-Dimethylaniline [121-69-7] (1993)

Dimethyl hydrogen phosphite [868-85-9] (1990)

1,4-Dimethylphenanthrene [22349-59-3]

1,3-Dinitropyrene [75321-20-9] (1989)

Dinitrosopentamethylenetetramine [101-25-7]

2,4´-Diphenyldiamine [492-17-1]

Disperse Yellow 3 [2832-40-8] (1990)

Disulfiram [97-77-8]

Dithranol [1143-38-0]

Doxefazepam [40762-15-0] (1996)

Droloxifene [82413-20-5] (1996)

Dulcin [150-69-6]

Endrin [72-20-8]

Eosin [15086-94-9]

1,2-Epoxybutane [106-88-7] (1989)

3,4-Epoxy-6-methylcyclohexylmethyl-3,4-epoxy-6-methylcyclohexane carboxylate [141-37-7]

cis-9,10-Epoxystearic acid [2443-39-2]

Estazolam [29975-16-4] (1996)

Ethionamide [536-33-4]

Ethylene [74-85-1] (1994)

Ethylene sulphide [420-12-2]

2-Ethylhexyl acrylate [103-11-7] (1994)

Ethyl selenac [5456-28-0]

Ethyl tellurac [20941-65-5]

Eugenol [97-53-0]

Evans blue [314-13-6]

Fast Green FCF [2353-45-9]

Fenvalerate [51630-58-1] (1991)

Ferbam [14484-64-1]

Ferric oxide [1309-37-1]

Fluometuron [2164-17-2]

Fluoranthene [206-44-0]

Fluorene [86-73-7]

Fluorescent lighting (1992)

Fluorides (inorganic, used in drinking-water)

5-Fluorouracil [51-21-8]

Furazolidone [67-45-8]

Furfural [98-01-1] (1995)

Furosemide (Frusemide) [54-31-9] (1990)

Gemfibrozil [25812-30-0] (1996)

Glass filaments (1988)

Glycidyl oleate [5431-33-4]

Glycidyl stearate [7460-84-6]

Guinea Green B [4680-78-8]

Gyromitrin [16568-02-8]

Haematite [1317-60-8]

HC Blue No. 2 [33229-34-4] (1993)

HC Red No. 3 [2871-01-4] (1993)

HC Yellow No. 4 [59820-43-8] (1993)

Hepatitis D virus (1993)

Hexachlorobutadiene [87-68-3]

Hexachloroethane [67-72-1]

Hexachlorophene [70-30-4]

Human T-cell lymphotropic virus type II (1996)

Hycanthone mesylate [23255-93-8]

Hydralazine [86-54-4]

Hydrochloric acid [7647-01-0] (1992)

Hydrochlorothiazide [58-93-5] (1990)

Hydrogen peroxide [7722-84-1]

Hydroquinone [123-31-9]

4-Hydroxyazobenzene [1689-82-3]

8-Hydroxyquinoline [148-24-3]

Hydroxysenkirkine [26782-43-4]

Hypochlorite salts (1991)

Iron-dextrin complex [9004-51-7]

Iron sorbitol-citric acid complex [1338-16-5]

Isatidine [15503-86-3]

Isonicotinic acid hydrazide (Isoniazid) [54-85-3]

Isophosphamide [3778-73-2]

Isopropanol [67-63-0]

Isopropyl oils

Isosafrole [120-58-1]

Jacobine [6870-67-3]

Kaempferol [520-18-3]

Lauroyl peroxide [105-74-8]

Lead, organo [75-74-1], [78-00-2]

Light Green SF [5141-20-8]

d-Limonene [5989-27-5] (1993)

Luteoskyrin [21884-44-6]

Malathion [121-75-5]

Maleic hydrazide [123-33-1]

Malonaldehyde [542-78-9]

Maneb [12427-38-2]

Mannomustine dihydrochloride [551-74-6]

Medphalan [13045-94-8]

Melamine [108-78-1]

6-Mercaptopurine [50-44-2]

Mercury [7439-97-6] and inorganic mercury compounds (1993)

Metabisulphites (1992)

Methotrexate [59-05-2]

Methoxychlor [72-43-5]

Methyl acrylate [96-33-3]

5-Methylangelicin [73459-03-7] plus ultraviolet A radiation

Methyl bromide [74-83-9]

Methyl carbamate [598-55-0]

Methyl chloride [74-87-3]

1-Methylchrysene [3351-28-8]

2-Methylchrysene [3351-32-4]

3-Methylchrysene [3351-31-3]

4-Methylchrysene [3351-30-2]

6-Methylchrysene [1705-85-7]

N-Methyl-N,4-dinitrosoaniline [99-80-9]

4,4´-Methylenebis(N,N-dimethyl)benzenamine [101-61-1]

4,4´-Methylenediphenyl diisocyanate [101-68-8]

2-Methylfluoranthene [33543-31-6]

3-Methylfluoranthene [1706-01-0]

Methylglyoxal [78-98-8] (1991)

Methyl iodide [74-88-4]

Methyl methacrylate [80-62-6] (1994)

N-Methylolacrylamide [90456-67-0] (1994)

Methyl parathion [298-00-0]

1-Methylphenanthrene [832-69-9]

7-Methylpyrido[3,4-c]psoralen [85878-62-2]

Methyl red [493-52-7]

Methyl selenac [144-34-3]

Modacrylic fibres

Monuron [150-68-5] (1991)

Morpholine [110-91-8] (1989)

Musk ambrette [83-66-9] (1996)

Musk xylene [81-15-2] (1996)

1,5-Naphthalenediamine [2243-62-1]

1,5-Naphthalene diisocyanate [3173-72-6]

1-Naphthylamine [134-32-7]

1-Naphthylthiourea (ANTU) [86-88-4]

Nithiazide [139-94-6]

5-Nitro-o-anisidine [99-59-2]

9-Nitroanthracene [602-60-8]

7-Nitrobenz[a]anthracene [20268-51-3] (1989

6-Nitrobenzo[a]pyrene [63041-90-7] (1989)

4-Nitrobiphenyl [92-93-3]

3-Nitrofluoranthene [892-21-7]

Nitrofural (Nitrofurazone) [59-87-0] (1990)

Nitrofurantoin [67-20-9] (1990)

1-Nitronaphthalene [86-57-7] (1989)

2-Nitronaphthalene [581-89-5] (1989)

3-Nitroperylene [20589-63-3] (1989)

2-Nitropyrene [789-07-1] (1989)

N´-Nitrosoanabasine [37620-20-5]

N-Nitrosoanatabine [71267-22-6]

N-Nitrosodiphenylamine [86-30-6]

p-Nitrosodiphenylamine [156-10-5]

N-Nitrosofolic acid [29291-35-8]

N-Nitrosoguvacine [55557-01-2]

N-Nitrosoguvacoline [55557-02-3]

N-Nitrosohydroxyproline [30310-80-6]

3-(N-Nitrosomethylamino)propionaldehyde [85502-23-4]

4-(N-Nitrosomethylamino)-4-(3-pyridyl)-1-butanal (NNA) [64091-90-3]

N-Nitrosoproline [7519-36-0]

5-Nitro-o-toluidine [99-55-8] (1990)

Nitrovin [804-36-4]

Nylon 6 [25038-54-4]

Oestradiol mustard [22966-79-6]

Oestrogen-progestin replacement therapy

Opisthorchis felineus (infection with) (1994)

Orange I [523-44-4]

Orange G [1936-15-8]

Oxyphenbutazone [129-20-4]

Palygorskite (attapulgite) [12174-11-7] (short fibres, <<5 micro-meters) (1997)

Paracetamol (Acetaminophen) [103-90-2] (1990)

Parasorbic acid [10048-32-5]

Parathion [56-38-2]

Patulin [149-29-1]

Penicillic acid [90-65-3]

Pentachloroethane [76-01-7]

Permethrin [52645-53-1] (1991)

Perylene [198-55-0]

Petasitenine [60102-37-6]

Phenanthrene [85-01-8]

Phenelzine sulphate [156-51-4]

Phenicarbazide [103-03-7]

Phenol [108-95-2] (1989)

Phenylbutazone [50-33-9]

m-Phenylenediamine [108-45-2]

p-Phenylenediamine [106-50-3]

N-Phenyl-2-naphthylamine [135-88-6]

o-Phenylphenol [90-43-7]

Picloram [1918-02-1] (1991)

Piperonyl butoxide [51-03-6]

Polyacrylic acid [9003-01-4]

Polychlorinated dibenzo-p-dioxins (other than 2,3,7,8-tetra-chlorodibenzo-p-dioxin) (1997)

Polychlorinated dibenzofurans (1997)

Polychloroprene [9010-98-4]

Polyethylene [9002-88-4]

Polymethylene polyphenyl isocyanate [9016-87-9]

Polymethyl methacrylate [9011-14-7]

Polypropylene [9003-07-0]

Polystyrene [9003-53-6]

Polytetrafluoroethylene [9002-84-0]

Polyurethane foams [9009-54-5]

Polyvinyl acetate [9003-20-7]

Polyvinyl alcohol [9002-89-5]

Polyvinyl chloride [9002-86-2]

Polyvinyl pyrrolidone [9003-39-8]

Ponceau SX [4548-53-2]

Potassium bis(2-hydroxyethyl)dithiocarbamate[23746-34-1]

Prazepam [2955-38-6] (1996)

Prednimustine [29069-24-7] (1990)

Prednisone [53-03-2]

Proflavine salts

Pronetalol hydrochloride [51-02-5]

Propham [122-42-9]

n-Propyl carbamate [627-12-3]

Propylene [115-07-1] (1994)

Ptaquiloside [87625-62-5]

Pyrene [129-00-0]

Pyrido[3,4-c]psoralen [85878-62-2]

Pyrimethamine [58-14-0]

Quercetin [117-39-5]

p-Quinone [106-51-4]

Quintozene (Pentachloronitrobenzene) [82-68-8]

Reserpine [50-55-5]

Resorcinol [108-46-3]

Retrorsine [480-54-6]

Rhodamine B [81-88-9]

Rhodamine 6G [989-38-8]

Riddelliine [23246-96-0]

Rifampicin [13292-46-1]

Ripazepam [26308-28-1] (1996)

Rugulosin [23537-16-8]

Saccharated iron oxide [8047-67-4]

Scarlet Red [85-83-6]

Schistosoma mansoni (infection with) (1994)

Selenium [7782-49-2] and selenium compounds

Semicarbazide hydrochloride [563-41-7]

Seneciphylline [480-81-9]

Senkirkine [2318-18-5]

Sepiolite [15501-74-3]

Shikimic acid [138-59-0]

Silica [7631-86-9], amorphous

Simazine [122-34-9] (1991)

Sodium chlorite [7758-19-2] (1991)

Sodium diethyldithiocarbamate [148-18-5]

Spironolactone [52-01-7]

Styrene-acrylonitrile copolymers [9003-54-7]

Styrene-butadiene copolymers [9003-55-8]

Succinic anhydride [108-30-5]

Sudan I [842-07-9]

Sudan II [3118-97-6]

Sudan III [85-86-9]

Sudan Brown RR [6416-57-5]

Sudan Red 7B [6368-72-5]

Sulphafurazole (Sulphisoxazole) [127-69-5]

Sulphamethoxazole [723-46-6]

Sulphites (1992)

Sulphur dioxide [7446-09-5] (1992)

Sunset Yellow FCF [2783-94-0]

Symphytine [22571-95-5]

Talc [14807-96-6], not containing asbestiform fibres

Tannic acid [1401-55-4] and tannins

Temazepam [846-50-4] (1996)

2,2´,5,5´-Tetrachlorobenzidine [15721-02-5]

1,1,1,2-Tetrachloroethane [630-20-6]

1,1,2,2-Tetrachloroethane [79-34-5]

Tetrachlorvinphos [22248-79-9]

Tetrafluoroethylene [116-14-3]

Tetrakis(hydroxymethyl)phosphonium salts (1990)

Theobromine [83-67-0] (1991)

Theophylline [58-55-9] (1991)

Thiouracil [141-90-2]

Thiram [137-26-8] (1991)

Titanium dioxide [13463-67-7] (1989)

Toluene [108-88-3] (1989)

Toremifene [89778-26-7] (1996)

Toxins derived from Fusarium graminearum, F. culmorum andF. crookwellense (1993)

Toxins derived from Fusarium sporotrichioides (1993)

Trichlorfon [52-68-6]

Trichloroacetic acid [76-03-9] (1995)

Trichloroacetonitrile [545-06-2] (1991)

1,1,1-Trichloroethane [71-55-6]

1,1,2-Trichloroethane [79-00-5] (1991)

Triethylene glycol diglydicyl ether [1954-28-5]

Trifluralin [1582-09-8] (1991)

4,4´,6-Trimethylangelicin [90370-29-9] plus ultravioletradiation

2,4,5-Trimethylaniline [137-17-7]

2,4,6-Trimethylaniline [88-05-1]

4,5´,8-Trimethylpsoralen [3902-71-4]

2,4,6-Trinitrotoluene [118-96-7] (1996)

Triphenylene [217-59-4]

Tris(aziridinyl)-p-benzoquinone (Triaziquone) [68-76-8]

Tris(1-aziridinyl)phosphine oxide [545-55-1]

2,4,6-Tris(1-aziridinyl)-s-triazine [51-18-3]

Tris(2-chloroethyl)phosphate [115-96-8] (1990)

1,2,3-Tris(chloromethoxy)propane [38571-73-2]

Tris(2-methyl-1-aziridinyl)phosphine oxide [57-39-6]

Vat Yellow 4 [128-66-5] (1990)

Vinblastine sulphate [143-67-9]

Vincristine sulphate [2068-78-2]

Vinyl acetate [108-05-4]

Vinyl chloride-vinyl acetate copolymers [9003-22-9]

Vinylidene chloride [75-35-4]

Vinylidene chloride-vinyl chloride copolymers [9011-06-7]

Vinylidene fluoride [75-38-7]

N-Vinyl-2-pyrrolidone [88-12-0]

Vinyl toluene [25013-15-4] (1994)

Wollastonite [13983-17-0]

Xylene [1330-20-7] (1989)

2,4-Xylidine [95-68-1]

2,5-Xylidine [95-78-3]

Yellow AB [85-84-7]

Yellow OB [131-79-3]

Zectran [315-18-4]

Zeolites [1318-02-1] other than erionite (clinoptilolite,phillipsite, mordenite, non-fibrous Japanese zeolite,synthetic zeolites) (1997)

Zineb [12122-67-7]

Ziram [137-30-4] (1991)

Mixtures

Betel quid, without tobacco

Bitumens [8052-42-4], steam-refined, cracking-residue and air-refined

Crude oil [8002-05-9] (1989)

Diesel fuels, distillate (light) (1989)

Fuel oils, distillate (light) (1989)

Jet fuel (1989)

Mate (1990)

Mineral oils, highly refined

Petroleum solvents (1989)

Printing inks (1996)

Tea (1991)

Terpene polychlorinates (StrobaneR) [8001-50-1]

Exposure circumstances

Flat-glass and specialty glass (manufacture of) (1993)

Hair colouring products (personal use of) (1993)

Leather goods manufacture

Leather tanning and processing

Lumber and sawmill industries (including logging)

Paint manufacture (occupational exposure in) (1989)

Pulp and paper manufacture

Group 4—Probably not carcinogenic to humans (1)

Caprolactam [105-60-2]

 

Back

The History of Occupational Exposure Limits

Over the past 40 years, many organizations in numerous countries have proposed occupational exposure limits (OELs) for airborne contaminants. The limits or guidelines that have gradually become the most widely accepted both in the United States and in most other countries are those issued annually by the American Conference of Governmental Industrial Hygienists (ACGIH), which are termed threshold limit values (TLVs) (LaNier 1984; Cook 1986; ACGIH 1994).

The usefulness of establishing OELs for potentially harmful agents in the working environment has been demonstrated repeatedly since their inception (Stokinger 1970; Cook 1986; Doull 1994). The contribution of OELs to the prevention or minimization of disease is now widely accepted, but for many years such limits did not exist, and even when they did, they were often not observed (Cook 1945; Smyth 1956; Stokinger 1981; LaNier 1984; Cook 1986).

It was well understood as long ago as the fifteenth century, that airborne dusts and chemicals could bring about illness and injury, but the concentrations and lengths of exposure at which this might be expected to occur were unclear (Ramazinni 1700).

As reported by Baetjer (1980), “early in this century when Dr. Alice Hamilton began her distinguished career in occupational disease, no air samples and no standards were available to her, nor indeed were they necessary. Simple observation of the working conditions and the illness and deaths of the workers readily proved that harmful exposures existed. Soon however, the need for determining standards for safe exposure became obvious.”

The earliest efforts to set an OEL were directed to carbon monoxide, the toxic gas to which more persons are occupationally exposed than to any other (for a chronology of the development of OELs, see figure 1. The work of Max Gruber at the Hygienic Institute at Munich was published in 1883. The paper described exposing two hens and twelve rabbits to known concentrations of carbon monoxide for up to 47 hours over three days; he stated that “the boundary of injurious action of carbon monoxide lies at a concentration in all probability of 500 parts per million, but certainly (not less than) 200 parts per million”. In arriving at this conclusion, Gruber had also inhaled carbon monoxide himself. He reported no symptoms or uncomfortable sensations after three hours on each of two consecutive days at concentrations of 210 parts per million and 240 parts per million (Cook 1986).

Figure 1. Chronology of occupational exposure levels (OELS).

The earliest and most extensive series of animal experiments on exposure limits were those conducted by K.B. Lehmann and others under his direction. In a series of publications spanning 50 years they reported on studies on ammonia and hydrogen chloride gas, chlorinated hydrocarbons and a large number of other chemical substances (Lehmann 1886; Lehmann and Schmidt-Kehl 1936).

Kobert (1912) published one of the earlier tables of acute exposure limits. Concentrations for 20 substances were listed under the headings: (1) rapidly fatal to man and animals, (2) dangerous in 0.5 to one hour, (3) 0.5 to one hour without serious disturbances and (4) only minimal symptoms observed. In his paper “Interpretations of permissible limits”, Schrenk (1947) notes that the “values for hydrochloric acid, hydrogen cyanide, ammonia, chlorine and bromine as given under the heading ‘only minimal symptoms after several hours’ in the foregoing Kobert paper agree with values as usually accepted in present-day tables of MACs for reported exposures”. However, values for some of the more toxic organic solvents, such as benzene, carbon tetrachloride and carbon disulphide, far exceeded those currently in use (Cook 1986).

One of the first tables of exposure limits to originate in the United States was that published by the US Bureau of Mines (Fieldner, Katz and Kenney 1921). Although its title does not so indicate, the 33 substances listed are those encountered in workplaces. Cook (1986) also noted that most of the exposure limits through the 1930s, except for dusts, were based on rather short animal experiments. A notable exception was the study of chronic benzene exposure by Leonard Greenburg of the US Public Health Service, conducted under the direction of a committee of the National Safety Council (NSC 1926). An acceptable exposure for human beings based on long-term animal experiments was derived from this work.

According to Cook (1986), for dust exposures, permissible limits established before 1920 were based on exposures of workers in the South African gold mines, where the dust from drilling operations was high in crystalline free silica. In 1916, an exposure limit of 8.5 million particles per cubic foot of air (mppcf) for the dust with an 80 to 90% quartz content was set (Phthisis Prevention Committee 1916). Later, the level was lowered to 5 mppcf. Cook also reported that, in the United States, standards for dust, also based on exposure of workers, were recommended by Higgins and co-workers following a study at the south-western Missouri zinc and lead mines in 1917. The initial level established for high quartz dusts was ten mppcf, appreciably higher than was established by later dust studies conducted by the US Public Health Service. In 1930, the USSR Ministry of Labour issued a decree that included maximum allowable concentrations for 12 industrial toxic substances.

The most comprehensive list of occupational exposure limits up to 1926 was for 27 substances (Sayers 1927). In 1935 Sayers and Dalle Valle published physiological responses to five concentrations of 37 substances, the fifth being the maximum allowable concentration for prolonged exposure. Lehmann and Flury (1938) and Bowditch et al. (1940) published papers that presented tables with a single value for repeated exposures to each substance.

Many of the exposure limits developed by Lehmann were included in a monograph initially published in 1927 by Henderson and Haggard (1943), and a little later in Flury and Zernik’s Schadliche Gase (1931). According to Cook (1986), this book was considered the authoritative reference on effects of injurious gases, vapours and dusts in the workplace until Volume II of Patty’s Industrial Hygiene and Toxicology (1949) was published.

The first lists of standards for chemical exposures in industry, called maximum allowable concentrations (MACs), were prepared in 1939 and 1940 (Baetjer 1980). They represented a consensus of opinion of the American Standard Association and a number of industrial hygienists who had formed the ACGIH in 1938. These “suggested standards” were published in 1943 by James Sterner. A committee of the ACGIH met in early 1940 to begin the task of identifying safe levels of exposure to workplace chemicals, by assembling all the data which would relate the degree of exposure to a toxicant to the likelihood of producing an adverse effect (Stokinger 1981; LaNier 1984). The first set of values were released in 1941 by this committee, which was composed of Warren Cook, Manfred Boditch (reportedly the first hygienist employed by industry in the United States), William Fredrick, Philip Drinker, Lawrence Fairhall and Alan Dooley (Stokinger 1981).

In 1941, a committee (designated as Z-37) of the American Standards Association, which later became the American National Standards Institute, developed its first standard of 100 ppm for carbon monoxide. By 1974 the committee had issued separate bulletins for 33 exposure standards for toxic dusts and gases.

At the annual meeting of the ACGIH in 1942, the newly appointed Subcommittee on Threshold Limits presented in its report a table of 63 toxic substances with the “maximum allowable concentrations of atmospheric contaminants” from lists furnished by the various state industrial hygiene units. The report contains the statement, “The table is not to be construed as recommended safe concentrations. The material is presented without comment” (Cook 1986).

In 1945 a list of 132 industrial atmospheric contaminants with maximum allowable concentrations was published by Cook, including the then current values for six states, as well as values presented as a guide for occupational disease control by federal agencies and maximum allowable concentrations that appeared best supported by the references on original investigations (Cook 1986).

At the 1946 annual meeting of ACGIH, the Subcommittee on Threshold Limits presented their second report with the values of 131 gases, vapours, dusts, fumes and mists, and 13 mineral dusts. The values were compiled from the list reported by the subcommittee in 1942, from the list published by Warren Cook in Industrial Medicine (1945) and from published values of the Z-37 Committee of the American Standards Association. The committee emphasized that the “list of M.A.C. values is presented … with the definite understanding that it be subject to annual revision.”

Intended use of OELs

The ACGIH TLVs and most other OELs used in the United States and some other countries are limits which refer to airborne concentrations of substances and represent conditions under which “it is believed that nearly all workers may be repeatedly exposed day after day without adverse health effects” (ACGIH 1994). (See table 1).  In some countries the OEL is set at a concentration which will protect virtually everyone. It is important to recognize that unlike some exposure limits for ambient air pollutants, contaminated water, or food additives set by other professional groups or regulatory agencies, exposure to the TLV will not necessarily prevent discomfort or injury for everyone who is exposed (Adkins et al. 1990). The ACGIH recognized long ago that because of the wide range in individual susceptibility, a small percentage of workers may experience discomfort from some substances at concentrations at or below the threshold limit and that a smaller percentage may be affected more seriously by aggravation of a pre-existing condition or by development of an occupational illness (Cooper 1973; ACGIH 1994). This is clearly stated in the introduction to the ACGIH’s annual booklet Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices (ACGIH 1994).

Table 1. Occupational exposure limits (OELs) in various countries (as of 1986)

Source: Cook 1986.

This limitation, although perhaps less than ideal, has been considered a practical one since airborne concentrations so low as to protect hypersusceptibles have traditionally been judged infeasible due to either engineering or economic limitations. Until about 1990, this shortcoming in the TLVs was not considered a serious one. In light of the dramatic improvements since the mid-1980s in our analytical capabilities, personal monitoring/sampling devices, biological monitoring techniques and the use of robots as a plausible engineering control, we are now technologically able to consider more stringent occupational exposure limits.

The background information and rationale for each TLV are published periodically in the Documentation of the Threshold Limit Values (ACGIH 1995). Some type of documentation is occasionally available for OELs set in other countries. The rationale or documentation for a particular OEL should always be consulted before interpreting or adjusting an exposure limit, as well as the specific data that were considered in establishing it (ACGIH 1994).

TLVs are based on the best available information from industrial experience and human and animal experimental studies—when possible, from a combination of these sources (Smith and Olishifski 1988; ACGIH 1994). The rationale for choosing limiting values differs from substance to substance. For example, protection against impairment of health may be a guiding factor for some, whereas reasonable freedom from irritation, narcosis, nuisance or other forms of stress may form the basis for others. The age and completeness of the information available for establishing occupational exposure limits also varies from substance to substance; consequently, the precision of each TLV is different. The most recent TLV and its documentation (or its equivalent) should always be consulted in order to evaluate the quality of the data upon which that value was set.

Even though all of the publications which contain OELs emphasize that they were intended for use only in establishing safe levels of exposure for persons in the workplace, they have been used at times in other situations. It is for this reason that all exposure limits should be interpreted and applied only by someone knowledgeable of industrial hygiene and toxicology. The TLV Committee (ACGIH 1994) did not intend that they be used, or modified for use:

• as a relative index of hazard or toxicity
• in the evaluation of community air pollution
• for estimating the hazards of continuous, uninterrupted exposures or other extended work periods
• as proof or disproof of an existing disease or physical condition
• for adoption by countries whose working conditions differ from those of the United States.

 

The TLV Committee and other groups which set OELs warn that these values should not be “directly used” or extrapolated to predict safe levels of exposure for other exposure settings. However, if one understands the scientific rationale for the guideline and the appropriate approaches for extrapolating data, they can be used to predict acceptable levels of exposure for many different kinds of exposure scenarios and work schedules (ACGIH 1994; Hickey and Reist 1979).

Philosophy and approaches in setting exposure limits

TLVs were originally prepared to serve only for the use of industrial hygienists, who could exercise their own judgement in applying these values. They were not to be used for legal purposes (Baetjer 1980). However, in 1968 the United States Walsh-Healey Public Contract Act incorporated the 1968 TLV list, which covered about 400 chemicals. In the United States, when the Occupational Safety and Health Act (OSHA) was passed it required all standards to be national consensus standards or established federal standards.

Exposure limits for workplace air contaminants are based on the premise that, although all chemical substances are toxic at some concentration when experienced for a period of time, a concentration (e.g., dose) does exist for all substances at which no injurious effect should result no matter how often the exposure is repeated. A similar premise applies to substances whose effects are limited to irritation, narcosis, nuisance or other forms of stress (Stokinger 1981; ACGIH 1994).

This philosophy thus differs from that applied to physical agents such as ionizing radiation, and for some chemical carcinogens, since it is possible that there may be no threshold or no dose at which zero risk would be expected (Stokinger 1981). The issue of threshold effects is controversial, with reputable scientists arguing both for and against threshold theories (Seiler 1977; Watanabe et al. 1980, Stott et al. 1981; Butterworth and Slaga 1987; Bailer et al. 1988; Wilkinson 1988; Bus and Gibson 1994). With this in mind, some occupational exposure limits proposed by regulatory agencies in the early 1980s were set at levels which, although not completely without risk, posed risks that were no greater than classic occupational hazards such as electrocution, falls, and so on. Even in those settings which do not use industrial chemicals, the overall workplace risks of fatal injury are about one in one thousand. This is the rationale that has been used to justify selecting this theoretical cancer risk criterion for setting TLVs for chemical carcinogens (Rodricks, Brett and Wrenn 1987; Travis et al. 1987).

Occupational exposure limits established both in the United States and elsewhere are derived from a wide variety of sources. The 1968 TLVs (those adopted by OSHA in 1970 as federal regulations) were based largely on human experience. This may come as a surprise to many hygienists who have recently entered the profession, since it indicates that, in most cases, the setting of an exposure limit has come after a substance has been found to have toxic, irritational or otherwise undesirable effects on humans. As might be anticipated, many of the more recent exposure limits for systemic toxins, especially those internal limits set by manufacturers, have been based primarily on toxicology tests conducted on animals, in contrast to waiting for observations of adverse effects in exposed workers (Paustenbach and Langner 1986). However, even as far back as 1945, animal tests were acknowledged by the TLV Committee to be very valuable and they do, in fact, constitute the second most common source of information upon which these guidelines have been based (Stokinger 1970).

Several approaches for deriving OELs from animal data have been proposed and put into use over the past 40 years. The approach used by the TLV Committee and others is not markedly different from that which has been used by the US Food and Drug Administration (FDA) in establishing acceptable daily intakes (ADI) for food additives. An understanding of the FDA approach to setting exposure limits for food additives and contaminants can provide good insight to industrial hygienists who are involved in interpreting OELs (Dourson and Stara 1983).

Discussions of methodological approaches which can be used to establish workplace exposure limits based exclusively on animal data have also been presented (Weil 1972; WHO 1977; Zielhuis and van der Kreek 1979a, 1979b; Calabrese 1983; Dourson and Stara 1983; Leung and Paustenbach 1988a; Finley et al. 1992; Paustenbach 1995). Although these approaches have some degree of uncertainty, they seem to be much better than a qualitative extrapolation of animal test results to humans.

Approximately 50% of the 1968 TLVs were derived from human data, and approximately 30% were derived from animal data. By 1992, almost 50% were derived primarily from animal data. The criteria used to develop the TLVs may be classified into four groups: morphological, functional, biochemical and miscellaneous (nuisance, cosmetic). Of those TLVs based on human data, most are derived from effects observed in workers who were exposed to the substance for many years. Consequently, most of the existing TLVs have been based on the results of workplace monitoring, compiled with qualitative and quantitative observations of the human response (Stokinger 1970; Park and Snee 1983). In recent times, TLVs for new chemicals have been based primarily on the results of animal studies rather than human experience (Leung and Paustenbach 1988b; Leung et al. 1988).

It is noteworthy that in 1968 only about 50% of the TLVs were intended primarily to prevent systemic toxic effects. Roughly 40% were based on irritation and about two per cent were intended to prevent cancer. By 1993, about 50% were meant to prevent systemic effects, 35% to prevent irritation, and five per cent to prevent cancer. Figure 2 provides a summary of the data often used in developing OELs. 

Figure 2. Data often used in developing an occupational exposure.

Limits for irritants

Prior to 1975, OELs designed to prevent irritation were largely based on human experiments. Since then, several experimental animal models have been developed (Kane and Alarie 1977; Alarie 1981; Abraham et al. 1990; Nielsen 1991). Another model based on chemical properties has been used to set preliminary OELs for organic acids and bases (Leung and Paustenbach 1988).

Limits for carcinogens

In 1972, the ACGIH Committee began to distinguish between human and animal carcinogens in its TLV list. According to Stokinger (1977), one reason for this distinction was to assist the stakeholders in discussions (union representatives, workers and the public) in focusing on those chemicals with more probable workplace exposures.

Do the TLVs Protect Enough Workers?

Beginning in 1988, concerns were raised by numerous persons regarding the adequacy or health protectiveness of TLVs. The key question raised was, what percentage of the working population is truly protected from adverse health effects when exposed to the TLV?

Castleman and Ziem (1988) and Ziem and Castleman (1989) argued both that the scientific basis of the standards was inadequate and that they were formulated by hygienists with vested interests in the industries being regulated.

These papers engendered an enormous amount of discussion, both supportive of and opposed to the work of the ACGIH (Finklea 1988; Paustenbach 1990a, 1990b, 1990c; Tarlau 1990).

A follow-up study by Roach and Rappaport (1990) attempted to quantify the safety margin and scientific validity of the TLVs. They concluded that there were serious inconsistencies between the scientific data available and the interpretation given in the 1976 Documentation by the TLV Committee. They also note that the TLVs were probably reflective of what the Committee perceived to be realistic and attainable at the time. Both the Roach and Rappaport and the Castleman and Ziem analyses have been responded to by the ACGIH, who have insisted on the inaccuracy of the criticisms.

Although the merit of the Roach and Rappaport analysis, or for that matter, that of Ziem and Castleman, will be debated for a number of years, it is clear that the process by which TLVs and other OELs will be set will probably never be as it was between 1945 and 1990. It is likely that in coming years, the rationale, as well as the degree of risk inherent in a TLV, will be more explicitly described in the documentation for each TLV. Also, it is certain that the definition of “virtually safe” or “insignificant risk” with respect to workplace exposure will change as the values of society change (Paustenbach 1995, 1997).

The degree of reduction in TLVs or other OELs that will undoubtedly occur in the coming years will vary depending on the type of adverse health effect to be prevented (central nervous system depression, acute toxicity, odour, irritation, developmental effects, or others). It is unclear to what degree the TLV committee will rely on various predictive toxicity models, or what risk criteria they will adopt, as we enter the next century.

Standards and Nontraditional Work Schedules

The degree to which shift work affects a worker’s capabilities, longevity, mortality, and overall well-being is still not well understood. So-called nontraditional work shifts and work schedules have been implemented in a number of industries in an attempt to eliminate, or at least reduce, some of the problems caused by normal shift work, which consists of three eight-hour work shifts per day. One kind of work schedule which is classified as nontraditional is the type involving work periods longer than eight hours and varying (compressing) the number of days worked per week (e.g., a 12-hours-per-day, three-day workweek). Another type of nontraditional work schedule involves a series of brief exposures to a chemical or physical agent during a given work schedule (e.g., a schedule where a person is exposed to a chemical for 30 minutes, five times per day with one hour between exposures). The last category of nontraditional schedule is that involving the “critical case” wherein persons are continuously exposed to an air contaminant (e.g., spacecraft, submarine).

Compressed workweeks are a type of nontraditional work schedule that has been used primarily in non-manufacturing settings. It refers to full-time employment (virtually 40 hours per week) which is accomplished in less than five days per week. Many compressed schedules are currently in use, but the most common are: (a) four-day workweeks with ten-hour days; (b) three-day workweeks with 12-hour days; (c) 4-1/2–day workweeks with four nine-hour days and one four-hour day (usually Friday); and (d) the five/four, nine plan of alternating five-day and four-day workweeks of nine-hour days (Nollen and Martin 1978; Nollen 1981).

Of all workers, those on nontraditional schedules represent only about 5% of the working population. Of this number, only about 50,000 to 200,000 Americans who work nontraditional schedules are employed in industries where there is routine exposure to significant levels of airborne chemicals. In Canada, the percentage of chemical workers on nontraditional schedules is thought to be greater (Paustenbach 1994).

One Approach to Setting International OELs

As noted by Lundberg (1994), a challenge facing all national committees is to identify a common scientific approach to setting OELs. Joint international ventures are advantageous to the parties involved since writing criteria documents is both a time- and cost-consuming process (Paustenbach 1995).

This was the idea when the Nordic Council of Ministers in 1977 decided to establish the Nordic Expert Group (NEG). The task of the NEG was to develop scientifically-based criteria documents to be used as a common scientific basis of OELs by the regulatory authorities in the five Nordic countries (Denmark, Finland, Iceland, Norway and Sweden). The criteria documents from the NEG lead to the definition of a critical effect and dose-response/dose-effect relationships. The critical effect is the adverse effect that occurs at the lowest exposure. There is no discussion of safety factors and a numerical OEL is not proposed. Since 1987, criteria documents are published by the NEG concurrently in English on a yearly basis.

Lundberg (1994) has suggested a standardized approach that each county would use. He suggested building a document with the following characteristics:

• A standardized criteria document should reflect the up-to-date knowledge as presented in the scientific literature.
• The literature used should preferably be peer-reviewed scientific papers but at least be available publicly. Personal communications should be avoided. An openness toward the general public, particularly workers, decreases the kind of suspiciousness that recently has been addressed toward documentation from the ACGIH.
• The scientific committee should consist of independent scientists from academia and government. If the committee should include scientific representatives from the labour market, both employers and employees should be represented.
• All relevant epidemiological and experimental studies should be thoroughly scrutinized by the scientific committee, especially “key studies” that present data on the critical effect. All observed effects should be described.
• Environmental and biological monitoring possibilities should be pointed out. It is also necessary to thoroughly scrutinize these data, including toxicokinetic data.
• Data permitting, the establishment of dose-response and dose-effect relationships should be stated. A no observable effect level (NOEL) or lowest observable effect level (LOEL) for each observed effect should be stated in the conclusion. If necessary, reasons should be given as to why a certain effect is the critical one. The toxicological significance of an effect is thereby considered.
• Specifically, mutagenic, carcinogenic and teratogenic properties should be pointed out as well as allergic and immunological effects.
• A reference list for all studies described should be given. If it is stated in the document that only relevant studies have been used, there is no need to give a list of references not used or why. On the other hand, it could be of interest to list those databases that have been used in the literature search.

 

There are in practice only minor differences in the way OELs are set in the various countries that develop them. It should, therefore, be relatively easy to agree upon the format of a standardized criteria document containing the key information. From this point, the decision as to the size of the margin of safety that is incorporated in the limit would then be a matter of national policy.

 

Back

Whereas the principles and methods of risk assessment for non-carcinogenic chemicals are similar in different parts of the world, it is striking that approaches for risk assessment of carcinogenic chemicals vary greatly. There are not only marked differences between countries, but even within a country different approaches are applied or advocated by various regulatory agencies, committees and scientists in the field of risk assessment. Risk assessment for non-carcinogens is rather consistent and pretty well established partly because of the long history and better understanding of the nature of toxic effects in comparison with carcinogens and a high degree of consensus and confidence by both scientists and the general public on methods used and their outcome.

For non-carcinogenic chemicals, safety factors were introduced to compensate for uncertainties in the toxicology data (which are derived mostly from animal experiments) and in their applicability to large, heterogeneous human populations. In doing so, recommended or required limits on safe human exposures were usually set at a fraction (the safety or uncertainty factor approach) of the exposure levels in animals that could be clearly documented as the no observed adverse effects level (NOAEL) or the lowest observed adverse effects level (LOAEL). It was then assumed that as long as human exposure did not exceed the recommended limits, the hazardous properties of chemical substances would not be manifest. For many types of chemicals, this practice, in somewhat refined form, continues to this day in toxicological risk assessment.

During the late 1960s and early 1970s regulatory bodies, starting in the United States, were confronted with an increasingly important problem for which many scientists considered the safety factor approach to be inappropriate, and even dangerous. This was the problem with chemicals that under certain conditions had been shown to increase the risk of cancers in humans or experimental animals. These substances were operationally referred to as carcinogens. There is still debate and controversy on the definition of a carcinogen, and there is a wide range of opinion about techniques to identify and classify carcinogens and the process of cancer induction by chemicals as well.

The initial discussion started much earlier, when scientists in the 1940s discovered that chemical carcinogens caused damage by a biological mechanism that was of a totally different kind from those that produced other forms of toxicity. These scientists, using principles from the biology of radiation-induced cancers, put forth what is referred to as the “non-threshold” hypothesis, which was considered applicable to both radiation and carcinogenic chemicals. It was hypothesized that any exposure to a carcinogen that reaches its critical biological target, especially the genetic material, and interacts with it, can increase the probability (the risk) of cancer development.

Parallel to the ongoing scientific discussion on thresholds, there was a growing public concern on the adverse role of chemical carcinogens and the urgent need to protect the people from a set of diseases collectively called cancer. Cancer, with its insidious character and long latency period together with data showing that cancer incidences in the general population were increasing, was regarded by the general public and politicians as a matter of concern that warranted optimal protection. Regulators were faced with the problem of situations in which large numbers of people, sometimes nearly the entire population, were or could be exposed to relatively low levels of chemical substances (in consumer products and medicines, at the workplace as well as in air, water, food and soils) that had been identified as carcinogenic in humans or experimental animals under conditions of relatively intense exposures.

Those regulatory officials were confronted with two fundamental questions which, in most cases, could not be fully answered using available scientific methods:

1.  What risk to human health exists in the range of exposure to chemicals below the relatively intense and narrow exposure range under which a cancer risk could be directly measured?
2.  What could be said about risks to human health when experimental animals were the only subjects in which risks for the development of cancer had been established?

 

Regulators recognized the need for assumptions, sometimes scientifically based but often also unsupported by experimental evidence. In order to achieve consistency, definitions and specific sets of assumptions were adapted that would be generically applied to all carcinogens.

Carcinogenesis Is a Multistage Process

Several lines of evidence support the conclusion that chemical carcinogenesis is a multistage process driven by genetic damage and epigenetic changes, and this theory is widely accepted in the scientific community all over the world (Barrett 1993). Although the process of chemical carcinogenesis is often separated into three stages—initiation, promotion and progression—the number of relevant genetic changes is not known.

Initiation involves the induction of an irreversibly altered cell and is for genotoxic carcinogens always equated with a mutational event. Mutagenesis as a mechanism of carcinogenesis was already hypothesized by Theodor Boveri in 1914, and many of his assumptions and predictions have subsequently been proven to be true. Because irreversible and self-replicating mutagenic effects can be caused by the smallest amount of a DNA-modifying carcinogen, no threshold is assumed. Promotion is the process by which the initiated cell expands (clonally) by a series of divisions, and forms (pre)neoplastic lesions. There is considerable debate as to whether during this promotion phase initiated cells undergo additional genetic changes.

Finally in the progression stage “immortality” is obtained and full malignant tumours can develop by influencing angiogenesis, escaping the reaction of the host control systems. It is characterized by invasive growth and frequently metastatic spread of the tumour. Progression is accompanied by additional genetic changes due to the instability of proliferating cells and selection.

Therefore, there are three general mechanisms by which a substance can influence the multistep carcinogenic process. A chemical can induce a relevant genetic alteration, promote or facilitate clonal expansion of an initiated cell or stimulate progression to malignancy by somatic and/or genetic changes.

Risk Assessment Process

Risk can be defined as the predicted or actual frequency of occurrence of an adverse effect on humans or the environment, from a given exposure to a hazard. Risk assessment is a method of systematically organizing the scientific information and its attached uncertainties for description and qualification of the health risks associated with hazardous substances, processes, actions or events. It requires evaluation of relevant information and selection of the models to be used in drawing inferences from that information. Further, it requires explicit recognition of uncertainties and appropriate acknowledgement that alternative interpretation of the available data may be scientifically plausible. The current terminology used in risk assessment was proposed in 1984 by the US National Academy of Sciences. Qualitative risk assessment changed into hazard characterization/identification and quantitative risk assessment was divided into the components dose-response, exposure assessment and risk characterization.

In the following section these components will be briefly discussed in view of our current knowledge of the process of (chemical) carcinogenesis. It will become clear that the dominant uncertainty in the risk assessment of carcinogens is the dose-response pattern at low dose levels characteristic for environmental exposure.

Hazard identification

This process identifies which compounds have the potential to cause cancer in humans—in other words it identifies their intrinsic genotoxic properties. Combining information from various sources and on different properties serves as a basis for classification of carcinogenic compounds. In general the following information will be used:

• epidemiological data (e.g., vinylchloride, arsenic, asbestos)
• animal carcinogenicity data
• genotoxic activity/DNA adduct formation
• mechanisms of action
• pharmacokinetic activity
• structure-activity relationships.

 

Classification of chemicals into groups based on the assessment of the adequacy of the evidence of carcinogenesis in animals or in man, if epidemiological data are available, is a key process in hazard identification. The best known schemes for categorizing carcinogenic chemicals are those of IARC (1987), EU (1991) and the EPA (1986). An overview of their criteria for classification (e.g., low-dose extrapolation methods) is given in table 1.

Table 1. Comparison of low-dose extrapolations procedures

 

One important issue in classifying carcinogens, with sometimes far-reaching consequences for their regulation, is the distinction between genotoxic and non-genotoxic mechanisms of action. The US Environmental Protection Agency (EPA) default assumption for all substances showing carcinogenic activity in animal experiments is that no threshold exists (or at least none can be demonstrated), so there is some risk with any exposure. This is com- monly referred to as the non-threshold assumption for genotoxic (DNA-damaging) compounds. The EU and many of its members, such as the United Kingdom, the Netherlands and Denmark, make a distinction between carcinogens that are genotoxic and those believed to produce tumours by non-genotoxic mechanisms. For genotoxic carcinogens quantitative dose-response estimation procedures are followed that assume no threshold, although the procedures might differ from those used by the EPA. For non-genotoxic substances it is assumed that a threshold exists, and dose-response procedures are used that assume a threshold. In the latter case, the risk assessment is generally based on a safety factor approach, similar to the approach for non-carcinogens.

It is important to keep in mind that these different schemes were developed to deal with risk assessments in different contexts and settings. The IARC scheme was not produced for regulatory purposes, although it has been used as a basis for developing regulatory guidelines. The EPA scheme was designed to serve as a decision point for entering quantitative risk assessment, whereas the EU scheme is currently used to assign a hazard (classification) symbol and risk phrases to the chemical's label. A more extended discussion on this subject is presented in a recent review (Moolenaar 1994) covering procedures used by eight governmental agencies and two often-cited independent organizations, the Inter- national Agency for Research on Cancer (IARC) and the American Conference of Governmental Industrial Hygienists (ACGIH).

The classification schemes generally do not take into account the extensive negative evidence that may be available. Also, in recent years a greater understanding of the mechanism of action of carcinogens has emerged. Evidence has accumulated that some mechanisms of carcinogenicity are species-specific and are not relevant for man. The following examples will illustrate this important phenomenon. First, it has been recently demonstrated in studies on the carcinogenicity of diesel particles, that rats respond with lung tumours to a heavy loading of the lung with particles. However, lung cancer is not seen in coal miners with very heavy lung burdens of particles. Secondly, there is the assertion of the nonrelevance of renal tumours in the male rat on the basis that the key element in the tumourgenic response is the accumulation in the kidney of α-2 microglobulin, a protein that does not exist in humans (Borghoff, Short and Swenberg 1990). Disturbances of rodent thyroid function and peroxisome proliferation or mitogenesis in the mouse liver have also to be mentioned in this respect.

This knowledge allows a more sophisticated interpretation of the results of a carcinogenicity bioassay. Research towards a better understanding of the mechanisms of action of carcinogenicity is encouraged because it may lead to an altered classification and to the addition of a category in which chemicals are classified as not carcinogenic to humans.

Exposure assessment

Exposure assessment is often thought to be the component of risk assessment with the least inherent uncertainty because of the ability to monitor exposures in some cases and the availability of relatively well-validated exposure models. This is only partially true, however, because most exposure assessments are not conducted in ways that take full advantage of the range of available information. For that reason there is a great deal of room for improving exposure distribution estimates. This holds for both external as well as for internal exposure assessments. Especially for carcinogens, the use of target tissue doses rather than external exposure levels in modelling dose-response relationships would lead to more relevant predictions of risk, although many assumptions on default values are involved. Physiologically based pharmacokinetic (PBPK) models to determine the amount of reactive metabolites that reaches the target tissue are potentially of great value to estimate these tissue doses.

Risk Characterization

Current approaches

The dose level or exposure level that causes an effect in an animal study and the likely dose causing a similar effect in humans is a key consideration in risk characterization. This includes both dose-response assessment from high to low dose and interspecies extrapolation. The extrapolation presents a logical problem, namely that data are being extrapolated many orders of magnitude below the experimental exposure levels by empirical models that do not reflect the underlying mechanisms for carcinogenicity. This violates a basic principle in fitting of empirical models, namely not to extrapolate outside the range of the observable data. Therefore, this empirical extrapolation results in large uncertainties, both from a statistical and from a biological point of view. At present no single mathematical procedure is recognized as the most appropriate one for low-dose extrapolation in carcinogenesis. The mathematical models that have been used to describe the relation between the administered external dose, the time and the tumour incidence are based on either tolerance-distribution or mechanistic assumptions, and sometimes based on both. A summary of the most frequently cited models (Kramer et al. 1995) is listed in table 2.

Table 2. Frequently cited models in carcinogen risk characterization

¹ Time-to-tumour models.

These dose-response models are usually applied to tumour-incidence data corresponding to only a limited number of experimental doses. This is due to the standard design of the applied bioassay. Instead of determining the complete dose-response curve, a carcinogenicity study is in general limited to three (or two) relatively high doses, using the maximum tolerated dose (MTD) as highest dose. These high doses are used to overcome the inherent low statistical sensitivity (10 to 15% over background) of such bioassays, which is due to the fact that (for practical and other reasons) a relatively small number of animals is used. Because data for the low-dose region are not available (i.e., cannot be determined experimentally), extrapolation outside the range of observation is required. For almost all data sets, most of the above-listed models fit equally well in the observed dose range, due to the limited number of doses and animals. However, in the low-dose region these models diverge several orders of magnitude, thereby introducing large uncertainties to the risk estimated for these low exposure levels.

Because the actual form of the dose-response curve in the low-dose range cannot be generated experimentally, mechanistic insight into the process of carcinogenicity is crucial to be able to discriminate on this aspect between the various models. Comprehensive reviews discussing the various aspects of the different mathematical extrapolation models are presented in Kramer et al. (1995) and Park and Hawkins (1993).

Other approaches

Besides the current practice of mathematical modelling several alternative approaches have been proposed recently.

Biologically motivated models

Currently, the biologically based models such as the Moolgavkar-Venzon-Knudson (MVK) models are very promising, but at present these are not sufficiently well advanced for routine use and require much more specific information than currently is obtained in bioassays. Large studies (4,000 rats) such as those carried out on N-nitrosoalkylamines indicate the size of the study which is required for the collection of such data, although it is still not possible to extrapolate to low doses. Until these models are further developed they can be used only on a case-by-case basis.

Assessment factor approach

The use of mathematical models for extrapolation below the experimental dose range is in effect equivalent to a safety factor approach with a large and ill-defined uncertainty factor. The simplest alternative would be to apply an assessment factor to the apparent “no effect level”, or the “lowest level tested”. The level used for this assessment factor should be determined on a case-by-case basis considering the nature of the chemical and the population being exposed.

Benchmark dose (BMD)

The basis of this approach is a mathematical model fitted to the experimental data within the observable range to estimate or interpolate a dose corresponding to a defined level of effect, such as one, five or ten per cent increase in tumour incidence (ED₀₁, ED₀₅, ED₁₀). As a ten per cent increase is about the smallest change that statistically can be determined in a standard bioassay, the ED₁₀ is appropriate for cancer data. Using a BMD that is within the observable range of the experiment avoids the problems associated with dose extrapolation. Estimates of the BMD or its lower confidence limit reflect the doses at which changes in tumour incidence occurred, but are quite insensitive to the mathematical model used. A benchmark dose can be used in risk assessment as a measure of tumour potency and combined with appropriate assessment factors to set acceptable levels for human exposure.

Threshold of regulation

Krewski et al. (1990) have reviewed the concept of a “threshold of regulation” for chemical carcinogens. Based on data obtained from the carcinogen potency database (CPDB) for 585 experiments, the dose corresponding to 10^-6 risk was roughly log-normally distributed around a median of 70 to 90 ng/kg/d. Exposure to dose levels greater than this range would be considered unacceptable. The dose was estimated by linear extrapolation from the TD₅₀ (the dose inducing toxicity is 50% of the animals tested) and was within a factor of five to ten of the figure obtained from the linearized multistage model. Unfortunately, the TD₅₀ values will be related to the MTD, which again casts doubt on the validity of the measurement. However the TD₅₀ will often be within or very close to the experimental data range.

Such an approach as using a threshold of regulation would require much more consideration of biological, analytical and mathematical issues and a much wider database before it could be considered. Further investigation into the potencies of various carcinogens may throw further light onto this area.

Objectives and Future of CarcinogenRisk Assessment

Looking back to the original expectations on the regulation of (environmental) carcinogens, namely to achieve a major reduction in cancer, it appears that the results at present are disappointing. Over the years it became apparent that the number of cancer cases estimated to be produced by regulatable carcinogens was disconcertingly small. Considering the high expectations that launched the regulatory efforts in the 1970s, a major anticipated reduction in the cancer death rate has not been achieved in terms of the estimated effects of environmental carcinogens, not even with ultraconservative quantitative assessment procedures. The main characteristic of the EPA procedures is that low-dose extrapolations are made in the same way for each chemical regardless of the mechanism of tumour formation in experimental studies. It should be noted, however, that this approach stands in sharp contrast to approaches taken by other governmental agencies. As indicated above, the EU and several European governments—Denmark, France, Germany, Italy, the Netherlands, Sweden, Switzerland, UK—distinguish between genotoxic and non-genotoxic carcinogens, and approach risk estimation differently for the two categories. In general, non-genotoxic carcinogens are treated as threshold toxicants. No effect levels are determined, and uncertainty factors are used to provide an ample margin of safety. To determine whether or not a chemical should be regarded as non-genotoxic is a matter of scientific debate and requires clear expert judgement.

The fundamental issue is: What is the cause of cancer in humans and what is the role of environmental carcinogens in that causation? The hereditary aspects of cancer in humans are much more important than previously anticipated. The key to signifi- cant advancement in the risk assessment of carcinogens is a better understanding of the causes and mechanisms of cancer. The field of cancer research is entering a very exciting area. Molecular research may radically alter the way we view the impact of environmental carcinogens and the approaches to control and prevent cancer, both for the general public and the workplace. Risk assessment of carcinogens needs to be based on concepts of the mechanisms of action that are, in fact, just emerging. One of the important aspects is the mechanism of heritable cancer and the interaction of carcinogens with this process. This knowledge will have to be incorporated into the systematic and consistent methodology that already exists for the risk assessment of carcinogens.

 

Back

An Integrated Approach in the Design of Workstations

In ergonomics, the design of workstations is a critical task. There is general agreement that in any work setting, whether blue-collar or white-collar, a well-designed workstation furthers not only the health and well-being of the workers, but also productivity and the quality of the products. Conversely, the poorly designed workstation is likely to cause or contribute to the development of health complaints or chronic occupational diseases, as well as to problems with keeping product quality and productivity at a prescribed level.

To every ergonomist, the above statement may seem trivial. It is also recognized by every ergonomist that working life worldwide is full of not only ergonomic shortcomings, but blatant violations of basic ergonomic principles. It is clearly evident that there is a widespread unawareness with respect to the importance of workstation design among those responsible: production engineers, supervisors and managers.

It is noteworthy that there is an international trend with respect to industrial work which would seem to underline the importance of ergonomic factors: the increasing demand for improved product quality, flexibility and product delivery precision. These demands are not compatible with a conservative view regarding the design of work and workplaces.

Although in the present context it is the physical factors of workplace design that are of chief concern, it should be borne in mind that the physical design of the workstation cannot in practice be separated from the organization of work. This principle will be made evident in the design process described in what follows. The quality of the end result of the process relies on three supports: ergonomic knowledge, integration with productivity and quality demands, and participation. The process of implementation of a new workstation must cater to this integration, and it is the main focus of this article.

Design considerations

Workstations are meant for work. It must be recognized that the point of departure in the workstation design process is that a certain production goal has to be achieved. The designer—often a production engineer or other person at middle-management level—develops internally a vision of the workplace, and starts to implement that vision through his or her planning media. The process is iterative: from a crude first attempt, the solutions become gradually more and more refined. It is essential that ergonomic aspects be taken into account in each iteration as the work progresses.

It should be noted that ergonomic design of workstations is closely related to ergonomic assessment of workstations. In fact, the structure to be followed here applies equally to the cases where the workstation already exists or when it is in a planning stage.

In the design process, there is a need for a structure which ensures that all relevant aspects be considered. The traditional way to handle this is to use checklists containing a series of those variables which should be taken into account. However, general purpose checklists tend to be voluminous and difficult to use, since in a particular design situation only a fraction of the checklist may be relevant. Furthermore, in a practical design situation, some variables stand out as being more important than others. A methodology to consider these factors jointly in a design situation is required. Such a methodology will be proposed in this article.

Recommendations for workstation design must be based on a relevant set of demands. It should be noted that it is in general not enough to take into account threshold limit values for individual variables. A recognized combined goal of productivity and conservation of health makes it necessary to be more ambitious than in a traditional design situation. In particular, the question of musculoskeletal complaints is a major aspect in many industrial situations, although this category of problems is by no means limited to the industrial environment.

A Workstation Design Process

Steps in the process

In the workstation design and implementation process, there is always an initial need to inform users and to organize the project so as to allow for full user participation and in order to increase the chance of full employee acceptance of the final result. A treatment of this goal is not within the scope of the present treatise, which concentrates on the problem of arriving at an optimal solution for the physical design of the workstation, but the design process nonetheless allows the integration of such a goal. In this process, the following steps should always be considered:

1. collection of user-specified demands
2. prioritizing of demands
3. transfer of demands into (a) technical specifications and (b) specifications in user terms
4. iterative development of the workstation’s physical layout
5. physical implementation
6. trial period of production
7. full production
8. evaluation and identification of rest problems.

 

The focus here is on steps one through five. Many times, only a subset of all these steps is actually included in the design of workstations. There may be various reasons for this. If the workstation is a standard design, such as in some VDU working situations, some steps may duly be excluded. However, in most cases the exclusion of some of the steps listed would lead to a workstation of lower quality than what can be considered acceptable. This can be the case when economic or time constraints are too severe, or when there is sheer neglect due to lack of knowledge or insight at management level.

Collection of user-specified demands

It is essential to identify the user of the workplace as any member of the production organization who may be able to contribute qualified views on its design. Users may include, for instance, the workers, the supervisors, the production planners and production engineers, as well as the safety steward. Experience shows clearly that these actors all have their unique knowledge which should be made use of in the process.

The collection of the user-specified demands should meet a number of criteria:

1. Openness. There should be no filter applied in the initial stage of the process. All points of view should be noted without voiced criticism.
2. Non-discrimination. Viewpoints from every category should be treated equally at this stage of the process. Special consideration should be given to the fact that some persons may be more outspoken than others, and that there is a risk that they may silence some of the other actors.
3. Development through dialogue. There should be an opportunity to adjust and develop the demands through a dialogue between participants of different backgrounds. Prioritizing should be addressed as part of the process.
4. Versatility. The process of collection of user-specified demands should be reasonably economical and not require the involvement of specialist consultants or extensive time demands on the part of the participants.

 

The above set of criteria may be met by using a methodology based on quality function deployment (QFD) according to Sullivan (1986). Here, the user demands may be collected in a session where a mixed group of actors (not more than eight to ten people) is present. All participants are given a pad of removable self-sticking notes. They are asked to write down all workplace demands which they find relevant, each one on a separate slip of paper. Aspects relating to work environment and safety, productivity and quality should be covered. This activity may continue for as long as found necessary, typically ten to fifteen minutes. After this session, one after the other of the participants is asked to read out his or her demands and to stick the notes on a board in the room where everyone in the group can see them. The demands are grouped into natural categories such as lighting, lifting aids, production equipment, reaching requirements and flexibility demands. After the completion of the round, the group is given the opportunity to discuss and to comment on the set of demands, one category at a time, with respect to relevance and priority.

The set of user-specified demands collected in a process such as the one described in the above forms one of the bases for the development of the demand specification. Additional information in the process may be produced by other categories of actors, for example, product designers, quality engineers, or economists; however, it is vital to realize the potential contribution that the users can make in this context.

Prioritizing and demand specification

With respect to the specification process, it is essential that the different types of demands be given consideration according to their respective importance; otherwise, all aspects that have been taken into account will have to be considered in parallel, which may tend to make the design situation complex and difficult to handle. This is why checklists, which need to be elaborate if they are to serve the purpose, tend to be difficult to manage in a particular design situation.

It may be difficult to devise a priority scheme which serves all types of workstations equally well. However, on the assumption that manual handling of materials, tools or products is an essential aspect of the work to be carried out in the workstation, there is a high probability that aspects associated with musculoskeletal load will be at the top of the priority list. The validity of this assumption may be checked in the user demand collection stage of the process. Relevant user demands may be, for instance, associated with muscular strain and fatigue, reaching, seeing, or ease of manipulation.

It is essential to realize that it may not be possible to transform all user-specified demands into technical demand specifications. Although such demands may relate to more subtle aspects such as comfort, they may nevertheless be of high relevance and should be considered in the process.

Musculoskeletal load variables

In line with the above reasoning, we shall here apply the view that there is a set of basic ergonomic variables relating to musculoskeletal load which need to be taken into account as a priority in the design process, in order to eliminate the risk of work-related musculosketal disorders (WRMDs). This type of disorder is a pain syndrome, localized in the musculoskeletal system, which develops over long periods of time as a result of repeated stresses on a particular body part (Putz-Anderson 1988). The essential variables are (e.g., Corlett 1988):

• muscular force demand

• working posture demand

• time demand.

 

With respect to muscular force, criteria setting may be based on a combination of biomechanical, physiological and psychological factors. This is a variable that is operationalized through measurement of output force demands, in terms of handled mass or required force for, say, the operation of handles. Also, peak loads in connection with highly dynamic work may have to be taken into account.

Working posture demands may be evaluated by mapping (a) situations where the joint structures are stretched beyond the natural range of movement, and (b) certain particularly awkward situations, such as kneeling, twisting, or stooped postures, or work with the hand held above shoulder level.

Time demands may be evaluated on the basis of mapping (a) short-cycle, repetitive work, and (b) static work. It should be noted that static work evaluation may not exclusively concern maintaining a working posture or producing a constant output force over lengthy periods of time; from the point of view of the stabilizing muscles, particularly in the shoulder joint, seemingly dynamic work may have a static character. It may thus be necessary to consider lengthy periods of joint mobilization.

The acceptability of a situation is of course based in practice on the demands on the part of the body that is under the highest strain.

It is important to note that these variables should not be considered one at a time but jointly. For instance, high force demands may be acceptable if they occur only occasionally; lifting the arm above shoulder level once in a while is not normally a risk factor. But combinations among such basic variables must be considered. This tends to make criteria setting difficult and involved.

In the Revised NIOSH equation for the design and evaluation of manual handling tasks (Waters et al. 1993), this problem is addressed by devising an equation for recommended weight limits which takes into account the following mediating factors: horizontal distance, vertical lifting height, lifting asymmetry, handle coupling and lifting frequency. In this way, the 23-kilogram acceptable load limit based on biomechanical, physiological and psychological criteria under ideal conditions, may be modified substantially upon taking into account the specifics of the working situation. The NIOSH equation provides a base for evaluation of work and workplaces involving lifting tasks. However, there are severe limitations as to the usability of the NIOSH equation: for instance, only two-handed lifts may be analysed; scientific evidence for analysis of one-handed lifts is still inconclusive. This illustrates the problem of applying scientific evidence exclusively as a basis for work and workplace design: in practice, scientific evidence must be merged with educated views of persons who have direct or indirect experience of the type of work considered.

The cube model

Ergonomic evaluation of workplaces, taking into account the complex set of variables which need to be considered, is to a large extent a communications problem. Based on the prioritizing discussion described above, a cube model for ergonomic evaluation of workplaces was developed (Kadefors 1993). Here the prime goal was to develop a didactic tool for communication purposes, based on the assumption that output force, posture and time measures in a great majority of situations constitute interrelated, prioritized basic variables.

For each one of the basic variables, it is recognized that the demands may be grouped with respect to severity. Here, it is proposed that such a grouping may be made in three classes: (1) low demands, (2) medium demands or (3) high demands. The demand levels may be set either by using whatever scientific evidence is available or by taking a consensus approach with a panel of users. These two alternatives are of course not mutually exclusive, and may well entail similar results, but probably with different degrees of generality.

As noted above, combinations of the basic variables determine to a large extent the risk level with respect to the development of musculoskeletal complaints and cumulative trauma disorders. For instance, high time demands may render a working situation unacceptable in cases where there are also at least medium level demands with respect to force and posture. It is essential in the design and assessment of workplaces that the most important variables be considered jointly. Here a cube model for such evaluation purposes is proposed. The basic variables—force, posture and time—constitute the three axes of the cube. For each combination of demands a subcube may be defined; in all, the model incorporates 27 such subcubes (see figure 1).

Figure 1. The "cube model" for ergonomics assessment. Each cube represents a combination of demands relating to force, posture and time. Light: acceptable combination; gray: conditionally acceptable; black: unacceptable

An essential aspect of the model is the degree of acceptability of the demand combinations. In the model, a three-zone classification scheme is proposed for acceptability: (1) the situation is acceptable, (2) the situation is conditionally acceptable or (3) the situation is unacceptable. For didactic purposes, each subcube may be given a certain texture or colour (say, green-yellow-red). Again, the assessment may be user-based or based on scientific evidence. The conditionally acceptable (yellow) zone means that “there exists a risk of disease or injury that cannot be neglected, for the whole or a part of the operator population in question” (CEN 1994).

In order to develop this approach, it is useful to consider a case: the evaluation of load on the shoulder in moderately paced one-handed materials handling. This is a good example, since in this type of situation, it is normally the shoulder structures that are under the heaviest strain.

With respect to the force variable, classification may be based in this case on handled mass. Here, low force demand is identified as levels below 10% of maximal voluntary lifting capacity (MVLC), which amounts to approximately 1.6 kg in an optimal working zone. High force demand requires more than 30% MVLC, approximately 4.8 kg. Medium force demand falls in between these limits. Low postural strain is when the upper arm is close to the thorax. High postural strain is when humeral abduction or flexion exceeds 45°. Medium postural strain is when the abduction/flexion angle is between 15° and 45°. Low time demand is when the handling occupies less than one hour per working day on and off, or continuously for less than 10 minutes per day. High time demand is when the handling takes place for more than four hours per working day, or continuously for more than 30 minutes (sustained or repetitively). Medium time demand is when the exposure falls between these limits.

In figure 1, degrees of acceptability have been assigned to combinations of demands. For instance, it is seen that high time demands may only be combined with combined low force and postural demands. Moving from unacceptable to acceptable may be undertaken by reducing demands in either dimension, but reduction in time demands is the most efficient way in many cases. In other words, in some cases workplace design should be altered, in other cases it may be more efficient to change the organization of work.

Using a consensus panel with a set of users for definition of demand levels and classification of degree of acceptability may enhance the workstation design process considerably, as considered below.

Additional variables

In addition to the basic variables considered above, a set of variables and factors characterizing the workplace from an ergonomics point of view has to be taken into account, depending upon the particular conditions of the situation to be analysed. They include:

• precautions to reduce risks for accidents

• specific environmental factors such as noise, lighting and ventilation

• exposure to climatic factors

• exposure to vibration (from hand-held tools or whole body)

• ease of meeting productivity and quality demands.

 

To a large extent these factors may be considered one at a time; hence the checklist approach may be useful. Grandjean (1988) in his textbook covers the essential aspects that usually need to be taken into account in this context. Konz (1990) in his guidelines provides for workstation organization and design a set of leading questions focusing on worker-machine interfacing in manufacturing systems.

In the design process followed here, the checklist should be read in conjunction with the user-specified demands.

A Workstation Design Example: Manual Welding

As an illustrative (hypothetical) example, the design process leading to implementation of a workstation for manual welding (Sundin et al. 1994) is described here. Welding is an activity frequently combining high demands for muscular force with high demands for manual precision. The work has a static character. The welder is often doing welding exclusively. The welding work environment is generally hostile, with a combination of exposure to high noise levels, welding smoke and optical radiation.

The task was to devise a workplace for manual MIG (metal inert gas) welding of medium size objects (up to 300 kg) in a workshop environment. The workstation had to be flexible since there was a variety of objects to be manufactured. There were high demands for productivity and quality.

A QFD process was carried out in order to provide a set of workstation demands in user terms. Welders, production engineers and product designers were involved. User demands, which are not listed here, covered a wide range of aspects including ergonomics, safety, productivity and quality.

Using the cube model approach, the panel identified, by consensus, limits between high, moderate and low load:

1. Force variable. Less than 1 kg handled mass is termed a low load, whereas more than 3 kg is considered a high load.
2. Postural strain variable. Working positions implying high strain are those involving elevated arms, twisted or deep forward-flexed positions, and kneeling positions, and also include situations where the wrist is held in extreme flexion/extension or deviation. Low strain occurs where the posture is straight upright standing or sitting and where hands are in optimal working zones.
3. Time variable. Less than 10% of the working time devoted to welding is considered low demand, whereas more than 40% of total working time is termed high demand. Medium demands occur when the variable falls between the limits given above, or when the situation is unclear.

 

It was clear from assessment using the cube model (figure 1) that high time demands could not be accepted if there were concurrent high or moderate demands in terms of force and postural strain. In order to reduce these demands, mechanized object handling and tool suspension was deemed a necessity. There was consensus developed around this conclusion. Using a simple computer-aided design (CAD) program (ROOMER), an equipment library was created. Various workplace station layouts could be developed very easily and modified in close interaction with the users. This design approach has significant advantages compared with merely looking at plans. It gives the user an immediate vision of what the intended workplace may look like.

Figure 2.  A CAD version of a workstation for manual welding, arrived at in the design process

Figure 2 shows the welding workstation arrived at using the CAD system. It is a workplace which reduces the force and posture demands, and which meets nearly all the residual user demands put forward.

 

 

 

 

 

Figure 3. The welding workstation implemented

On the basis of the results of the first stages of the design process, a welding workplace (figure 3) was implemented. Assets of this workplace include:

1. Work in the optimized zone is facilitated using a computerized handling device for welding objects. There is an overhead hoist for transportation purposes. As an alternative, a balanced lifting device is supplied for easy object handling.
2. The welding gun and grinding machine are suspended, thus reducing force demands. They can be positioned anywhere around the welding object. A welding chair is supplied.
3. All media come from above, which means that there are no cables on the floor.
4. The workstation has lighting at three levels: general, workplace and process. The workplace lighting comes from ramps above the wall elements. The process lighting is integrated in the welding smoke ventilation arm.
5. The workstation has ventilation at three levels: general displacement ventilation, workplace ventilation using a movable arm, and integrated ventilation in the MIG welding gun. The workplace ventilation is controlled from the welding gun.
6. There are noise-absorbing wall elements on three sides of the workplace. A transparent welding curtain covers the fourth wall. This makes it possible for the welder to keep informed of what happens in the workshop environment.

 

In a real design situation, compromises of various kinds may have to be made, due to economic, space and other constraints. It should be noted, however, that licensed welders are hard to come by for the welding industry around the world, and they represent a considerable investment. Nearly no welders go into normal retirement as active welders. Keeping the skilled welder on the job is beneficial for all parties involved: welder, company and society. For instance, there are very good reasons why equipment for object handling and positioning should be an integral constituent of many welding workplaces.

Data for Workstation Design

In order to be able to design a workplace properly, extensive sets of basic information may be needed. Such information includes anthropometric data of user categories, lifting strength and other output force capacity data of male and female populations, specifications of what constitutes optimal working zones and so forth. In the present article, references to some key papers are given.

The most complete treatment of virtually all aspects of work and workstation design is probably still the textbook by Grandjean (1988). Information on a wide range of anthropometric aspects relevant to workstation design is presented by Pheasant (1986). Large amounts of biomechanical and anthropometric data are given by Chaffin and Andersson (1984). Konz (1990) has presented a practical guide to workstation design, including many useful rules of thumb. Evaluation criteria for the upper limb, particularly with reference to cumulative trauma disorders, have been presented by Putz-Anderson (1988). An assessment model for work with hand tools was given by Sperling et al. (1993). With respect to manual lifting, Waters and co-workers have developed the revised NIOSH equation, summarizing existing scientific knowledge on the subject (Waters et al. 1993). Specification of functional anthropometry and optimal working zones have been presented by, for example, Rebiffé, Zayana and Tarrière (1969) and Das and Grady (1983a, 1983b). Mital and Karwowski (1991) have edited a useful book reviewing various aspects relating in particular to the design of industrial workplaces.

The large amount of data needed to design workstations properly, taking all relevant aspects into account, will make necessary the use of modern information technology by production engineers and other responsible people. It is likely that various types of decision-support systems will be made available in the near future, for instance in the form of knowledge-based or expert systems. Reports on such developments have been given by, for example, DeGreve and Ayoub (1987), Laurig and Rombach (1989), and Pham and Onder (1992). However, it is an extremely difficult task to devise a system making it possible for the end-user to have easy access to all relevant data needed in a specific design situation.

 

Back