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27. Formaldehyde Risk Assessment

Author

Crump, Kenny S., Chen, Chao, Fox, John F., Subramaniam, Ravi, and Van Landingham, Cynthia

Published
2009

32. Extended Analysis and Evidence Integration of Chloroprene as a Human Carcinogen.

Author

Sax, Sonja N, Gentry, P. Robinan, Van Landingham, Cynthia, Clewell, Harvey J., and Mundt, Kenneth A.

Subjects
CHLOROPRENE, CARCINOGENS, ELASTOMERS, VINYL chloride, MULTIPLE tumors
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. [ABSTRACT FROM AUTHOR]

Published
2020
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34. CHANG ET AL. REPLY

Author

Chang, Ellen T, primary, Lau, Edmund C, additional, Van Landingham, Cynthia, additional, Crump, Kenny S, additional, McClellan, Roger O, additional, and Moolgavkar, Suresh H, additional

Published
2018
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37. A tissue dose-based comparative exposure assessment of manganese using physiologically based pharmacokinetic modeling-The importance of homeostatic control for an essential metal.

Author

UCL - SSS/IREC/LTAP - Louvain Centre for Toxicology and Applied Pharmacology, Gentry, P Robinan, Van Landingham, Cynthia, Fuller, William G, Sulsky, Sandra I, Greene, Tracy B, Clewell, Harvey J, Andersen, Melvin E, Roels, Harry, Taylor, Michael D, Keene, Athena M, UCL - SSS/IREC/LTAP - Louvain Centre for Toxicology and Applied Pharmacology, Gentry, P Robinan, Van Landingham, Cynthia, Fuller, William G, Sulsky, Sandra I, Greene, Tracy B, Clewell, Harvey J, Andersen, Melvin E, Roels, Harry, Taylor, Michael D, and Keene, Athena M

Abstract

A physiologically-based pharmacokinetic (PBPK) model (Schroeter et al., 2011) was applied to simulate target tissue manganese (Mn) concentrations following occupational and environmental exposures. These estimates of target tissue Mn concentrations were compared to determine margins of safety (MOS) and to evaluate the biological relevance of applying safety factors to derive acceptable Mn air concentrations. Mn blood concentrations measured in occupational studies permitted verification of the human PBPK models, increasing confidence in the resulting estimates. Mn exposure was determined based on measured ambient air Mn concentrations and dietary data in Canada and the United States (US). Incorporating dietary and inhalation exposures into the models indicated that increases in target tissue concentrations above endogenous levels only begin to occur when humans are exposed to levels of Mn in ambient air (i.e. >10μg/m) that are far higher than those currently measured in Canada or the US. A MOS greater than three orders of magnitude was observed, indicating that current Mn air concentrations are far below concentrations that would be required to produce the target tissue Mn concentrations associated with subclinical neurological effects. This application of PBPK modeling for an essential element clearly demonstrates that the conventional application of default factors to "convert" an occupational exposure to an equivalent continuous environmental exposure, followed by the application of safety factors, is not appropriate in the case of Mn. PBPK modeling demonstrates that the relationship between ambient Mn exposures and dose-to-target tissue is not linear due to normal tissue background levels and homeostatic controls.

Published
2017

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