Chloroform carcinogenicity: a focused reassessment of mode of action evidence informing low-dose extrapolation

U.S. EPA’s final 2001 Integrated Risk Information System (IRIS) Toxicological Review of Chloroform, based largely on data from oral exposures, concluded that chloroform induces tumor formation that is secondary to sustained or repeated cytotoxicity and regenerative hyperplasia. The weight of evidence evaluation concluded that a “mutagenic mode of action (MOA) via DNA reactivity is not a significant component of the chloroform carcinogenic process,” and that chloroform is a threshold carcinogen and there is no need to default to linear low-dose extrapolation to estimate cancer risk at environmentally relevant low exposures. The IRIS Program is currently undertaking a reassessment of the health effects of chloroform via inhalation exposure and is asking the question: “Does newly identified literature change the 2001 conclusion that chloroform is a threshold carcinogen?” A systematic evidence map (SEM) of the chloroform evidence base through early 2022 was generated by conducting a literature search then screening studies to identify those consistent with data considered supplemental to the defined Populations, Exposure, Comparators and Outcomes (PECO) criteria. Mechanistic endpoints were reviewed and analyzed and less than 10 new studies informing the genotoxic potential for chloroform were identified, with only 3 studies addressing mutagenicity specifically. Further evaluation of these studies will inform a key science issue being addressed in the draft IRIS reassessment of Chloroform: Is the threshold-based MOA conclusion is still supported or does newly identified data support changing to the more conservative and protective linear low-dose extrapolation to estimate cancer risk from exposure to Chloroform.

Impact/Purpose

U.S. EPA’s final 2001 Integrated Risk Information System (IRIS) Toxicological Review of Chloroform, based largely on data from oral exposures, concluded that chloroform induces tumor formation that is secondary to sustained or repeated cytotoxicity and regenerative hyperplasia. The weight of evidence evaluation concluded that a “mutagenic mode of action (MOA) via DNA reactivity is not a significant component of the chloroform carcinogenic process,” and that chloroform is a threshold carcinogen and there is no need to default to linear low-dose extrapolation to estimate cancer risk at environmentally relevant low exposures. The IRIS Program is currently undertaking a reassessment of the health effects of chloroform via inhalation exposure and is asking the question: “Does newly identified literature change the 2001 conclusion that chloroform is a threshold carcinogen?” A systematic evidence map (SEM) of the chloroform evidence base through early 2022 was generated by conducting a literature search then screening studies to identify those consistent with data considered supplemental to the defined Populations, Exposure, Comparators and Outcomes (PECO) criteria. Mechanistic endpoints were reviewed and analyzed and less than 10 new studies informing the genotoxic potential for chloroform were identified, with only 3 studies addressing mutagenicity specifically. Further evaluation of these studies will inform a key science issue being addressed in the draft IRIS reassessment of Chloroform: Is the threshold-based MOA conclusion is still supported or does newly identified data support changing to the more conservative and protective linear low-dose extrapolation to estimate cancer risk from exposure to Chloroform.

Citation

Pratt, M., C. Keshava, A. Mudipalli, Andre Weaver, Nagalakshmi Keshava, A. Galizia, AND K. Thayer. Chloroform carcinogenicity: a focused reassessment of mode of action evidence informing low-dose extrapolation. 13th International Conference on Environmental Mutagens-Maintaining Genomic Health in a Changing World; 53rd Annual Meeting of the EMGS, Ottawa, Ontario, CANADA, August 27 - September 01, 2022.