Extended Analysis and Evidence Integration of Chloroprene as a Human Carcinogen

Abstract

β‐Chloroprene is used in the production of polychloroprene, a synthetic rubber. In 2010, Environmental Protection Agency (EPA) published the Integrated Risk Information System “Toxicological Review of Chloroprene,” concluding that chloroprene was “likely to be carcinogenic to humans.” This was based on findings from a 1998 National Toxicology Program (NTP) study showing multiple tumors within and across animal species; results from occupational epidemiological studies; a proposed mutagenic mode of action; and structural similarities with 1,3‐butadiene and vinyl chloride. Using mouse data from the NTP study and assuming a mutagenic mode of action, EPA calculated an inhalation unit risk (IUR) for chloroprene of 5 × 10−4 per µg/m3. This is among the highest IURs for chemicals classified by IARC or EPA as known or probable human carcinogens and orders of magnitude higher than the IURs for carcinogens such as vinyl chloride, benzene, and 1,3‐butadiene. Due to differences in pharmacokinetics, mice appear to be uniquely responsive to chloroprene exposure compared to other animals, including humans, which is consistent with the lack of evidence of carcinogenicity in robust occupational epidemiological studies. We evaluated and integrated all lines of evidence for chloroprene carcinogenicity to assess whether the 2010 EPA IUR could be scientifically substantiated. Due to clear interspecies differences in carcinogenic response to chloroprene, we applied a physiologically based pharmacokinetic model for chloroprene to calculate a species‐specific internal dose (amount metabolized/gram of lung tissue) and derived an IUR that is over 100‐fold lower than the 2010 EPA IUR. Therefore, we recommend that EPA's IUR be updated.

Ethylene Oxide: Cancer Evidence Integration and Dose–Response Implications

“…A similar pattern was seen in studies conducted by Marsh et al 66,67 on chloroprene exposure and risk of both lung and liver cancers, where overall slight deficits appeared to be driven by clear deficits in the lowest exposure group. 68 These observations raise important methodological questions regarding the underlying dose–response relationship and whether the risk deficits observed among the lowest exposure groups reflect a protective effect, chance, or some form of study bias. Considering that many epidemiologists assume that the cancer rate in the lowest exposure group (often without validating this assumption), the potential problem may be more widespread.…”