Carcinogenicity and mode of action evaluation for alpha-hexachlorocyclohexane: Implications for human health risk assessment

Autor: Judi Durda, Ann E. Bradley, Joanna L. Shoenfelt
Rok vydání: 2016
Předmět:
Male
0301 basic medicine
Insecticides
Time Factors
Hexachlorocyclohexane
010501 environmental sciences
Pharmacology
Toxicology
01 natural sciences
Mice
chemistry.chemical_compound
Human health
Human relevance
Threshold
Liver Neoplasms
General Medicine
Dose-response
Cell Transformation
Neoplastic
Liver
Mode of action
Female
Risk assessment
Alpha-hexachlorocyclohexane
Carcinoma
Hepatocellular
Carcinogenicity Tests
Nonlinear
Biology
Models
Biological
Risk Assessment
03 medical and health sciences
Sex Factors
Species Specificity
Liver carcinogenesis
Animals
Humans
Carcinogen
Cell Proliferation
0105 earth and related environmental sciences
Reference dose
No-Observed-Adverse-Effect Level
Dose-Response Relationship
Drug
Liver Carcinogenesis
alpha-Hexachlorocyclohexane
Rats
030104 developmental biology
Nonlinear Dynamics
chemistry
Linear Models
Zdroj: Regulatory Toxicology and Pharmacology. 76:152-173
ISSN: 0273-2300
Popis: 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.
Databáze: OpenAIRE
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