title: Carcinogenicity and mode of action evaluation for alpha-hexachlorocyclohexane: Implications for human health risk assessment.
abstract: Alpha-hexachlorocyclohexane (alpha-HCH) is one of eight structural isomers that have been used worldwide as insecticides. Although no longer produced or used agriculturally in the United States, exposure to HCH isomers is of continuing concern due to legacy usage and persistence in the environment. The U.S. Environmental Protection Agency (EPA) classifies alpha-HCH as a probable human carcinogen and provides a slope factor of 6.3 (mg/kg-day)(-1) for the compound, based on hepatic nodules and hepatocellular carcinomas observed in male mice and derived using a default linear approach for modeling carcinogens. EPA's evaluation, last updated in 1993, does not consider more recently available guidance that allows for the incorporation of mode of action (MOA) for determining a compound's dose-response. Contrary to the linear approach assumed by EPA, the available data indicate that alpha-HCH exhibits carcinogenicity via an MOA that yields a nonlinear, threshold dose-response. In our analysis, we conducted an MOA evaluation and dose-response analysis for alpha-HCH-induced liver carcinogenesis. We concluded that alpha-HCH causes liver tumors in rats and mice through an MOA involving increased promotion of cell growth, or mitogenesis. Based on these findings, we developed a threshold, cancer-based, reference dose (RfD) for alpha-HCH.
authors.affiliation: Integral Consulting Inc., USA. Electronic address: abradley@integral-corp.com.
authors.forename: Ann E
authors.initials: AE
authors.lastname: Bradley
authors.affiliation: Integral Consulting Inc., USA.
authors.forename: Joanna L
authors.initials: JL
authors.lastname: Shoenfelt
authors.affiliation: Integral Consulting Inc., USA.
authors.forename: Judi L
authors.initials: JL
authors.lastname: Durda
mesh_terms: D000818:Animals; D015197:Carcinogenicity Tests; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D001556:Hexachlorocyclohexane / Q000633:toxicity*; D006801:Humans; D007306:Insecticides / Q000633:toxicity*; D016014:Linear Models; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D051379:Mice; D008954:Models, Biological; D019055:No-Observed-Adverse-Effect Level; D017711:Nonlinear Dynamics; D051381:Rats; D018570:Risk Assessment; D012737:Sex Factors; D013045:Species Specificity; D013997:Time Factors
chemical_list: D007306:Insecticides; C040534:alpha-hexachlorocyclohexane; D001556:Hexachlorocyclohexane
keywords: Alpha-hexachlorocyclohexane; Dose-response; Hexachlorocyclohexane; Human relevance; Liver carcinogenesis; Mode of action; Nonlinear; Reference dose; Threshold