HEXACHLOROCYCLOHEXANE (TECHNICAL HCH AND LINDANE)

VOL.: 20 (1979) (p. 195)

5. Summary of Data Reported and Evaluation

5.1 Experimental data

α-HCH was tested in several experiments in mice by oral administration: it produced benign and malignant liver tumours in animals of both sexes; a treatment of 16 weeks was sufficient to produce tumours. Two feeding experiments in rats, one of which suggested a carcinogenic effect on the liver, were considered to be inadequate.

β-HCH was tested in four experiments in mice by oral administration: two were inadequate, and another was inadequately reported but suggested hepatocarcinogenicity; in the fourth study, β-HCH induced benign and malignant liver tumours in animals of both sexes. Two feeding experiments in rats were considered to be inadequate.

Lindane was tested in six experiments in mice by oral administration: it produced benign and malignant liver tumours in animals of both sexes in two experiments, one of which involved only small groups of animals. The results of a third experiment suggested hepatocarcinogenicity but were inadequately reported. The results of a fourth experiment also suggested hepatocarcinogenicity but were considered inadequate because of the low number of control animals used. The other experiments were considered inadequate for an evaluation of carcinogenicity. Lindane was also tested in three feeding studies in rats: two were considered inadequate; in the other a slight excess of thyroid tumours was observed in females. Lindane was tested inadequately in mice by skin application and by subcutaneous and intraperitoneal administration.

Experimental data on the long-term effects of the d- and e-isomers were considered to be inadequate.

Technical HCH was tested in three experiments in mice by oral administration, producing liver tumours. A feeding experiment in rats was considered to be inadequate.

Lindane is embryotoxic. α- and β-HCH and lindane, when tested individually and/or as a mixture, were not mutagenic in bacteria, yeast or Drosophila. Lindane induces chromosome aberrations, polyploidy and mitotic arrest in a number of plant systems. It also induced chromatid breaks in human lymphocytes in vitro.

5.2 Human data

Several case reports indicate a relationship between exposure to HCH or lindane and the occurrence of aplastic anaemia. Two cases of acute myeloid-type leukaemia in cousins exposed to lindane and one case of acute myelomonocytic leukaemia, secondary to aplastic anaemia, that was associated with dermal exposure to a lindane/toxaphene mixture have also been reported.

The only epidemiological study related to possible carcinogenic effects of HCH or lindane in humans involved exposure to many pesticides; the Working Group was thus unable to draw any conclusion specific to HCH or lindane.

The extensive production of HCH and lindane and their use in veterinary, agricultural and consumer products since the early 1950s indicate that widespread human exposure occurs. This is confirmed by many reports of their occurrence in the general environment and by reports of their presence in body fluids and tissues, both in the general population and in exposed workers.

5.3 Evaluation

There is sufficient evidence that α-HCH, lindane and technical HCH are carcinogenic in mice; there is limited evidence that β-HCH is carcinogenic in mice.

For definition of the italicized terms, see Preamble Evaluation.

Previous evaluation: Vol. 5 (1974)

Subsequent evaluation: Suppl. 7 (1987)

IARC Monographs Programme on the Evaluation of Carcinogenic Risks to Humans

Last updated: 31 March 1998

http://193.51.164.11/htdocs/monographs/Vol20/Hexachlorocyclohexanes.html

For definition of Groups, see Preamble Evaluation.

Supplement 7: (1987) (p. 220)

Hexachlorocyclohexane [mixed isomers]
CAS No.: 608-73-1
Chem. Abstr. Name: 1,2,3,4,5,6-Hexachlorocyclohexane

Hexachlorocyclohexane [a-isomer]
CAS No.: 319-84-6
Chem. Abstr. Name: 1a,2a,3b,4a,5b,6a-Hexachlorocyclohexane

Hexachlorocyclohexane [b-isomer]
CAS No.: 319-85-7
Chem. Abstr. Name: 1a,2b,3a,4b,5a,6b-Hexachlorocyclohexane

Lindane
CAS No.: 58-89-9
Chem. Abstr. Name: 1a,2a,3b,4a,5a,6b-Hexachlorocyclohexane

Hexachlorocyclohexane [d-isomer]
CAS No.: 319-86-8
Chem. Abstr. Name: 1a,2a,3a,4b,5a,6b-Hexachlorocyclohexane

Hexachlorocyclohexane [e-isomer]
CAS No.: 6108-10-7
Chem. Abstr. Name: 1a,2a,3a,4b,5b,6b-Hexachlorocyclohexane

Hexachlorocyclohexane [z-isomer]
CAS No.: 6108-11-8
Chem. Abstr. Name: 1a,2a,3a,4a,5a,6a-Hexachlorocyclohexane

Hexachlorocyclohexane [h-isomer]
CAS No.: 6108-12-9
Chem. Abstr. Name: 1a,2a,3a,4a,5b,6b-Hexachlorocyclohexane

Hexachlorocyclohexane [q-isomer]
CAS No.: 6108-13-0
Chem. Abstr. Name: 1a,2a,3a,4a,5a,6b-

A. Evidence for carcinogenicity to humans (inadequate for hexachlorocyclohexanes)

Four cases of leukaemia were reported in men exposed to g-hexachlorocyclohexane (lindane) with or without other chemicals [ref: 1,2]. Cases of aplastic anaemia have also been associated with exposure to this compound [ref: 1]. Mean tissue levels of hexachlorocyclohexanes were reported to be elevated in two of three studies of autopsy patients; in one of these, in four liver cancer patients, the level of the b-isomer was abnormally high [ref: 3-5]. Mean serum levels of b-hexachlorocyclohexane were not appreciably higher in four cancer patients than in three controls [ref: 6]. Exposure to g-hexachlorocyclohexane was recorded in case-control studies of soft-tissue sarcomas and of lymphomas [ref: 7,8] but was insufficiently frequent for any conclusion to be drawn. An increase in lung cancer mortality was observed in agricultural workers who had used hexachlorocyclohexane (unspecified) and a variety of other pesticides and herbicides (standardized mortality ratio, 180 [95% confidence interval, 140-240]) [ref: 9].

B. Evidence for carcinogenicity to animals (sufficient for technical-grade and for the a isomer; limited for the b and for the g isomers)

Technical-grade, a- and b-hexachlorocyclohexane and the g isomer (lindane) produced liver tumours in mice when administered orally [ref: 1,10,11]; the technical grade also produced lymphoreticular neoplasms [ref: 10]. In two studies in rats, an increased incidence of liver tumours was observed with the a isomer [ref: 1,12], and in one study in rats a few thyroid tumours were observed with the g isomer [ref: 1]; other studies in rats [ref: 11,13-15] were considered to be inadequate. Studies in hamsters [ref: 11] and dogs [ref: 16] were also inadequate. Technical-grade hexachlorocyclohexane and the g isomer were tested inadequately by skin application in mice [ref: 1,10]. a-Hexachlorocyclohexane enhanced the incidence of liver neoplasms induced in rats by N-nitrosodiethylamine [ref: 12].

C. Other relevant data

In a single study, chromosomal aberrations were not found in workers involved in the production of g-hexachlorocyclohexane (lindane) [ref: 17].

Technical-grade hexachlorocyclohexane, but not g- hexachlorocyclohexane, induced dominant lethal mutations in mice; chromosomal aberrations were not found in bone-marrow cells of mice exposed to technical-grade or g-hexachlorocyclohexane in vivo. g-Hexachlorocyclohexane did not induce unscheduled DNA synthesis in human cells in vitro and did not induce micronuclei or chromosomal aberrations in cultured rodent cells; it induced DNA strand breaks but not unscheduled DNA synthesis. It inhibited intercellular communication in Chinese hamster V79 cells. It did not induce sex-linked recessive lethal mutations in Drosophila. a- Hexachlorocyclohexane was not mutagenic to yeast, but the gamma isomer induced gene conversion. Neither g- nor b-hexachlorocyclohexane was mutagenic to bacteria, and a- and b-hexachlorocyclohexane did not cause DNA damage in bacteria [ref: 17].

Overall evaluation

Hexacyclohexanes are possibly carcinogenic to humans (Group 2B).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluations: Vol. 5 (1974); Vol. 20 (1979)

References

1. IARC Monographs, 20, 195-239, 1979

2. Sidi, Y., Kiltchevsky, E., Shaklai, M. & Pinkhas, J. (1983) Acute myeloblastic leukemia and insecticide. N.Y. State J. Med., 83, 161

3. Hoffman, W.S., Adler, H., Fishbein, W.I. & Bauer, F.C. (1967) Relation of pesticide concentrations in fat to pathological changes in tissues. Arch. environ. Health, 15, 758-765

4. Radomski, J.L., Deichmann, W.B., Clizer, E.E. & Rey, A. (1968) Pesticide concentrations in the liver, brain and adipose tissue of terminal hospital patients. Food Cosmet. Toxicol., 6, 209-220

5. Kasai, A., Asanuma, S. & Nakamura, S. (1972) Studies on organochlorine pesticide residues in human organs. Part III (Jpn.). Nippon Noson Igakkai Zasshi, 21, 296-297

6. Caldwell, G.G., Cannon, S.B., Pratt, C.B. & Arthur, R.D. (1981) Serum pesticide levels in patients with childhood colorectal carcinoma. Cancer, 48, 774-778

7. Eriksson, M., Hardell, L., Berg, N.O., Möller, T. & Axelson, O. (1981) Soft-tissue sarcomas and exposure to chemical substances: a case-referent study. Br. J. ind. Med., 38, 27-33

8. Hardell, L., Eriksson, M., Lenner, P. & Lundgren, E. (1981) Malignant lymphoma and exposure to chemicals, especially organic solvents, chlorophenols and phenoxy acids: a case-control study. Br. J. Cancer, 43, 169-176

9. Barthel, E. (1981) Increased risk of lung cancer in pesticide-exposed male agricultural workers. J. Toxicol. environ. Health, 8, 1027-1040

10. Kashyap, S.K., Nigam, S.K., Gupta, R.C., Karnik, A.B. & Chatterjee, S.K. (1979) Carcinogenicity of hexachlorocyclohexane (BHC) in pure inbred Swiss mice. J. environ. Sci. Health, B14, 305-318

11. Munir, K.M., Soman, C.S. & Bhide, S.V. (1983) Hexachlorocyclohexane-induced tumorigenicity in mice under different experimental conditions. Tumori, 69, 383-386

12. Schulte-Hermann, R. & Parzefall, W. (1981) Failure to discriminate initiation from promotion of liver tumors in a long-term study with the phenobarbital-type inducer a-hexachlorocyclohexane and the role of sustained stimulation of hepatic growth and monooxygenases. Cancer Res., 41, 4140-4146

13. Angsubhakorn, S., Bhamarapravati, N., Romruen, K., Sahaphong, S. & Thamavit, W. (1977) Alpha benzene hexachloride inhibition of aflatoxin B₁-induced hepatocellular carcinoma. A preliminary report. Experientia, 34, 1069-1970

14. Hiasa, Y., Ohshima, M., Ohmori, T. & Murata, Y. (1978) Effect of a-benzene hexachloride on 2-fluorenylacetamide carcinogenesis in rats. Gann, 69, 423-426

15. Angsubhakorn, S., Bhamarapravati, N., Romruen, K., Sahaphong, S., Thamavit, W. & Miyamoto, M. (1981) Further study of alpha benzene hexachloride inhibition of aflatoxin B₁ hepatocarcinogenesis in rats. Br. J. Cancer, 43, 881-883

16. Rivett, K.F., Chesterman, H., Kellett, D.N., Newman, A.J. & Worden, A.N. (1978) Effects of feeding lindane to dogs for periods of up to 2 years. Toxicology, 9, 273-289

17. IARC Monographs, Suppl. 6, 333-335, 1987

Synonyms for Hexachlorocyclohexane [mixed isomers]

• Benzahex
• Benzex
• BHC
• Dol
• Dolmix
• FBHC
• HCCH
• Hexachlor
• Hexachloran
• Hexafor
• Hexyclan
• Kotol
• Soprocide

• a-Benzene hexachloride
• a-BHC
• a-HCH
• a-Hexachloran
• a-Hexachlorane
• a-Hexachlorcyclohexane
• a-1,2,3,4,5,6-Hexachlorcyclohexane
• a-Hexachlorocyclohexane
• a-1,2,3,4,5,6-Hexachlorocyclohexane
• a-Lindane

Synonyms for Hexachlorocyclohexane [b-isomer]

• b-Benzene hexachloride
• b-BHC
• b-HCH
• b-Hexachlorobenzene
• b-Hexachlorocyclohexane
• b-1,2,3,4,5,6-Hexachlorocyclohexane
• b-Lindane

• Aalindan
• Aficide
• Agrocide
• Agrocide III
• Agrocide WP
• Ameisenmittel Merck
• Ameisentod
• Aparasin
• Aphtiria
• Aplidal
• Arbitex
• BBH
• Ben-Hex
• Bentox 10
• g-Benzene hexachloride
• Bexol
• g-BHC
• Celanex
• Chloresene
• Codechine
• DBH
• Detmol-extrakt
• Devoran
• Dol granule
• Drill tox-spezial aglukon
• ENT 7796
• Entomoxan
• Forlin
• Gamacid
• Gamaphex
• Gammalin
• Gammalin 20
• Gammaterr
• Gammexane
• Gexane
• HCH
• g-HCH
• Heclotox
• Hexa
• Hexachloran
• Hexachloran-gamma
• Hexachlorane
• Hexachlorane-gamma
• g-Hexachlorobenzene
• g-Hexachlorocyclohexane
• g-1,2,3,4,5,6-Hexachlorocyclohexane
• Hexatox
• Hexaverm
• Hexicide
• Hexyclan
• HGI
• Hortex
• Isotox
• Jacutin
• Kokotine
• Kwell
• Lendine
• Lentox
• Lidenal
• Lindafor
• Lindagam
• g-Lindane
• Lindatox
• Lindosep
• Lintox
• Lorexane
• Milbol 49
• Mszycol
• Neo-scabicidol
• Nexen FB
• Nexit
• Nexit-stark
• Nexol-E
• Nicochloran
• Novigam
• Omnitox
• Ovadziak
• Owadziak
• Pedraczak
• Pflanzol
• Quellada
• Sang-gamma
• Silvanol
• Spritz-Rapidin
• Sprehpflanzol
• Streunex
• TAP 85
• Tri-6
• Viton

Synonyms for Hexachlorocyclohexane [d-isomer]

• d-Benzene hexachloride
• d-BHC
• d-HCH
• d-Hexachlorocyclohexane
• d-1,2,3,4,5,6-Hexachlorocyclohexane
• d-Lindane

Synonyms for Hexachlorocyclohexane [e-isomer]

• e-Benzene hexachloride
• e-BHC
• e-HCH
• e-Hexachlorocyclohexane
• e-1,2,3,4,5,6-Hexachlorocyclohexane
• e-Lindane

Synonyms for Hexachlorocyclohexane [z-isomer]

• z-Hexachlorocyclohexane
• z-Lindane

• h-Hexachlorocyclohexane
• h-Lindane

Synonym for Hexachlorocyclohexane [q-isomer]

• q-Hexachlorocyclohexane
• q-Lindane

12. Evaluation

Evaluations of the strength of the evidence for carcinogenicity arising from human and experimental animal data are made, using standard terms.

It is recognized that the criteria for these evaluations, described below, cannot encompass all of the factors that may be relevant to an evaluation of carcinogenicity. In considering all of the relevant scientific data, the Working Group may assign the agent, mixture or exposure circumstance to a higher or lower category than a strict interpretation of these criteria would indicate.

(a) Degrees of evidence for carcinogenicity in humans and in experimental animals and supporting evidence

These categories refer only to the strength of the evidence that an exposure is carcinogenic and not to the extent of its carcinogenic activity (potency) nor to the mechanisms involved. A classification may change as new information becomes available.

An evaluation of degree of evidence, whether for a single agent or a mixture, is limited to the materials tested, as defined physically, chemically or biologically. When the agents evaluated are considered by the Working Group to be sufficiently closely related, they may be grouped together for the purpose of a single evaluation of degree of evidence.

(i) Carcinogenicity in humans

The applicability of an evaluation of the carcinogenicity of a mixture, process, occupation or industry on the basis of evidence from epidemiological studies depends on the variability over time and place of the mixtures, processes, occupations and industries. The Working Group seeks to identify the specific exposure, process or activity which is considered most likely to be responsible for any excess risk. The evaluation is focused as narrowly as the available data on exposure and other aspects permit.

The evidence relevant to carcinogenicity from studies in humans is classified into one of the following categories:

Sufficient evidence of carcinogenicity: The Working Group considers that a causal relationship has been established between exposure to the agent, mixture or exposure circumstance and human cancer. That is, a positive relationship has been observed between the exposure and cancer in studies in which chance, bias and confounding could be ruled out with reasonable confidence.

Limited evidence of carcinogenicity: A positive association has been observed between exposure to the agent, mixture or exposure circumstance and cancer for which a causal interpretation is considered by the Working Group to be credible, but chance, bias or confounding could not be ruled out with reasonable confidence.

Inadequate evidence of carcinogenicity: The available studies are of insufficient quality, consistency or statistical power to permit a conclusion regarding the presence or absence of a causal association between exposure and cancer, or no data on cancer in humans are available.

Evidence suggesting lack of carcinogenicity: There are several adequate studies covering the full range of levels of exposure that human beings are known to encounter, which are mutually consistent in not showing a positive association between exposure to the agent, mixture or exposure circumstance and any studied cancer at any observed level of exposure. A conclusion of 'evidence suggesting lack of carcinogenicity' is inevitably limited to the cancer sites, conditions and levels of exposure and length of observation covered by the available studies. In addition, the possibility of a very small risk at the levels of exposure studied can never be excluded.

In some instances, the above categories may be used to classify the degree of evidence related to carcinogenicity in specific organs or tissues.

(ii) Carcinogenicity in experimental animals

The evidence relevant to carcinogenicity in experimental animals is classified into one of the following categories:

Sufficient evidence of carcinogenicity: The Working Group considers that a causal relationship has been established between the agent or mixture and an increased incidence of malignant neoplasms or of an appropriate combination of benign and malignant neoplasms in (a) two or more species of animals or (b) in two or more independent studies in one species carried out at different times or in different laboratories or under different protocols.

Exceptionally, a single study in one species might be considered to provide sufficient evidence of carcinogenicity when malignant neoplasms occur to an unusual degree with regard to incidence, site, type of tumour or age at onset.

Limited evidence of carcinogenicity: The data suggest a carcinogenic effect but are limited for making a definitive evaluation because, e.g. (a) the evidence of carcinogenicity is restricted to a single experiment; or (b) there are unresolved questions regarding the adequacy of the design, conduct or interpretation of the study; or (c) the agent or mixture increases the incidence only of benign neoplasms or lesions of uncertain neoplastic potential, or of certain neoplasms which may occur spontaneously in high incidences in certain strains.

Inadequate evidence of carcinogenicity: The studies cannot be interpreted as showing either the presence or absence of a carcinogenic effect because of major qualitative or quantitative limitations, or no data on cancer in experimental animals are available.

Evidence suggesting lack of carcinogenicity: Adequate studies involving at least two species are available which show that, within the limits of the tests used, the agent or mixture is not carcinogenic. A conclusion of evidence suggesting lack of carcinogenicity is inevitably limited to the species, tumour sites and levels of exposure studied.

(b) Other data relevant to the evaluation of carcinogenicity and its mechanisms

Other evidence judged to be relevant to an evaluation of carcinogenicity and of sufficient importance to affect the overall evaluation is then described. This may include data on preneoplastic lesions, tumour pathology, genetic and related effects, structure-activity relationships, metabolism and pharmacokinetics, physicochemical parameters and analogous biological agents.

Data relevant to mechanisms of the carcinogenic action are also evaluated. The strength of the evidence that any carcinogenic effect observed is due to a particular mechanism is assessed, using terms such as weak, moderate or strong. Then, the Working Group assesses if that particular mechanism is likely to be operative in humans. The strongest indications that a particular mechanism operates in humans come from data on humans or biological specimens obtained from exposed humans. The data may be considered to be especially relevant if they show that the agent in question has caused changes in exposed humans that are on the causal pathway to carcinogenesis. Such data may, however, never become available, because it is at least conceivable that certain compounds may be kept from human use solely on the basis of evidence of their toxicity and/or carcinogenicity in experimental systems.

For complex exposures, including occupational and industrial exposures, the chemical composition and the potential contribution of carcinogens known to be present are considered by the Working Group in its overall evaluation of human carcinogenicity. The Working Group also determines the extent to which the materials tested in experimental systems are related to those to which humans are exposed.

(c) Overall evaluation

Finally, the body of evidence is considered as a whole, in order to reach an overall evaluation of the carcinogenicity to humans of an agent, mixture or circumstance of exposure.

An evaluation may be made for a group of chemical compounds that have been evaluated by the Working Group. In addition, when supporting data indicate that other, related compounds for which there is no direct evidence of capacity to induce cancer in humans or in animals may also be carcinogenic, a statement describing the rationale for this conclusion is added to the evaluation narrative; an additional evaluation may be made for this broader group of compounds if the strength of the evidence warrants it.

The agent, mixture or exposure circumstance is described according to the wording of one of the following categories, and the designated group is given. The categorization of an agent, mixture or exposure circumstance is a matter of scientific judgement, reflecting the strength of the evidence derived from studies in humans and in experimental animals and from other relevant data.

• Group 1: The agent (mixture) is carcinogenic to humans.
  The exposure circumstance entails exposures that are carcinogenic to humans.

This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.

• Group 2

This category includes agents, mixtures and exposure circumstances for which, at one extreme, the degree of evidence of carcinogenicity in humans is almost sufficient, as well as those for which, at the other extreme, there are no human data but for which there is evidence of carcinogenicity in experimental animals. Agents, mixtures and exposure circumstances are assigned to either group 2A (probably carcinogenic to humans) or group 2B (possibly carcinogenic to humans) on the basis of epidemiological and experimental evidence of carcinogenicity and other relevant data.

• Group 2A: The agent (mixture) is probably carcinogenic to humans.
  The exposure circumstance entails exposures that are probably carcinogenic to humans.

This category is used when there is limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals. In some cases, an agent (mixture) may be classified in this category when there is inadequate evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals and strong evidence that the carcinogenesis is mediated by a mechanism that also operates in humans. Exceptionally, an agent, mixture or exposure circumstance may be classified in this category solely on the basis of limited evidence of carcinogenicity in humans.

• Group 2B: The agent (mixture) is possibly carcinogenic to humans.
  The exposure circumstance entails exposures that are possibly carcinogenic to humans.

This category is used for agents, mixtures and exposure circumstances for which there is limited evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate evidence of carcinogenicity in humans but there is sufficient evidence of carcinogenicity in experimental animals. In some instances, an agent, mixture or exposure circumstance for which there is inadequate evidence of carcinogenicity in humans but limited evidence of carcinogenicity in experimental animals together with supporting evidence from other relevant data may be placed in this group.

• Group 3: The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans.

This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals.

Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans.

Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.

• Group 4: The agent (mixture) is probably not carcinogenic to humans.

This category is used for agents or mixtures for which there is evidence suggesting lack of carcinogenicity in humans and in experimental animals. In some instances, agents or mixtures for which there is inadequate evidence of carcinogenicity in humans but evidence suggesting lack of carcinogenicity in experimental animals, consistently and strongly supported by a broad range of other relevant data, may be classified in this group.