Potential For Incorporation Of Genetic Polymorphism Data In Human Health Risk Assessment
This overview summarizes several EPA assessment publications evaluating the potential impact of genetic polymorphisms in ten metabolizing enzymes on the variability in enzyme function across ethnically diverse populations.
The toxicity of chemicals entering the body is governed by many factors. An individual’s ability to metabolize the chemical is of prime importance. In some cases, this metabolism increases chemical toxicity. In other cases, this metabolism can lead to chemical detoxification and excretion. An individual’s ability to metabolize environmental chemicals is influenced by their genetic makeup, as well as other factors. Numerous genetic variants (polymorphisms) have been identified in the enzymes that control metabolism. Study of the influence of these genetic polymorphisms on an individual’s chemical metabolism can aid in understanding how, and by how much, metabolism may vary in a diverse population. Together with information on polymorphism frequency, this information may be used to develop population distributions of chemical metabolism.
The work presented in this series of papers focuses on the contribution of genetic polymorphisms to the variability in host metabolism and defense mechanisms by evaluating polymorphisms in 10 enzyme systems including three Phase I metabolic enzymes (CYP2E1, CYP2D6, PON1), four Phase II metabolic enzymes (SULTs, UGTs, GSTs, NATs), and three detoxification enzymes (ALDH2, EH, NQO1). Most of these enzymes have influential polymorphisms that are of sufficient frequency in the population to create a large degree of variability in enzyme activity. Monte Carlo simulation of five of these enzymes (CYP2D6, GSTs, NATs, PON1, and ALDH2) indicates that substantial percentages of the population are more than 3.2 fold different than the median enzyme activity seen in the general population. This indicates that for these, and likely other enzymes identified in this series of papers, the conversion of genotypic information into enzyme variability distributions may provide useful input into modeling internal dose (with physiologically-based pharmacokinetic modeling, PBPK modeling) using Monte Carlo analyses approaches that better capture human variability in internal dose and risk. The population distributions developed in this project may be used in such PBPK modeling efforts.
The toxicity of chemicals entering the body is governed by many factors. An individual’s ability to metabolize the chemical is of prime importance. In some cases, this metabolism increases chemical toxicity. In other cases, this metabolism can lead to chemical detoxification and excretion. An individual’s ability to metabolize environmental chemicals is influenced by their genetic makeup, as well as other factors. Numerous genetic variants (polymorphisms) have been identified in the enzymes that control metabolism. Study of the influence of these genetic polymorphisms on an individual’s chemical metabolism can aid in understanding how, and by how much, metabolism may vary in a diverse population. Together with information on polymorphism frequency, this information may be used to develop population distributions of chemical metabolism.
The work presented in this series of papers focuses on the contribution of genetic polymorphisms to the variability in host metabolism and defense mechanisms by evaluating polymorphisms in 10 enzyme systems including three Phase I metabolic enzymes (CYP2E1, CYP2D6, PON1), four Phase II metabolic enzymes (SULTs, UGTs, GSTs, NATs), and three detoxification enzymes (ALDH2, EH, NQO1). Most of these enzymes have influential polymorphisms that are of sufficient frequency in the population to create a large degree of variability in enzyme activity. Monte Carlo simulation of five of these enzymes (CYP2D6, GSTs, NATs, PON1, and ALDH2) indicates that substantial percentages of the population are more than 3.2 fold different than the median enzyme activity seen in the general population. This indicates that for these, and likely other enzymes identified in this series of papers, the conversion of genotypic information into enzyme variability distributions may provide useful input into modeling internal dose (with physiologically-based pharmacokinetic modeling, PBPK modeling) using Monte Carlo analyses approaches that better capture human variability in internal dose and risk. The population distributions developed in this project may be used in such PBPK modeling efforts.
Impact/Purpose
The work presented in this series of papers focuses on the contribution of genetic polymorphisms to the variability in host metabolism and defense mechanisms by evaluating polymorphisms in 10 enzyme systems including three Phase I metabolic enzymes (CYP2E1, CYP2D6, PON1), four Phase II metabolic enzymes (SULTs, UGTs, GSTs, NATs), and three detoxification enzymes (ALDH2, EH, NQO1).Citation
U.S. EPA. Potential For Incorporation Of Genetic Polymorphism Data In Human Health Risk Assessment. U.S. Environmental Protection Agency, Washington, DC, 2010.History/Chronology
| Date | Description |
|---|---|
| 01- 2002-2010 | Project results are published in peer-reviewed journals. |
| 02- Sep 2010 | EPA releases this summary report. |
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- Potential for Incorporation of Genetic Polymorphism Data (Summary Report) (PDF) (7 pp, 60.5 KB, about PDF)
- Ginsberg G; Smolenski S; Hattis D; Sonawane B (2002). Population distribution of aldehyde dehydrogenase-2 genetic polymorphism: Implications for risk assessment. Regul Toxicol Pharmacol, 36: 297-309.
- Ginsberg G; et al (2009a). The influence of genetic polymorphisms on population variability in six xenobiotic-metabolizing enzymes. J Toxicol Environ Health B Crit Rev, 12: 307-333.
- Ginsberg G; et al (2009b). Genetic polymorphism in glutathione transferases (GST): Population distribution of GSTM1, T1, and P1 conjugating activity. J Toxicol Environ Health B Crit Rev, 12: 389-439.
- Ginsberg G; et al (2009c). Genetic polymorphism in paraoxonase 1 (PON1): Population distribution of PON1 activity. J Toxicol Environ Health B Crit Rev, 12: 473-507.
- Ginsberg G; et al (2010). Genetic polymorphism in metabolism and host defense enzymes: implications for human health risk assessment. Crit Rev Toxicol, 40(7):575-619.
- Neafsey P; Ginsberg G; Hattis D; Sonawane B (2009a). Genetic polymorphism in cytochrome P450 2D6 (CYP2D6): Population distribution of CYP2D6 activity. J Toxicol Environ Health B Crit Rev, 12: 334-361.
- Neafsey P; Ginsberg G; Hattis D; Johns DO; Guyton KZ; Sonawane B (2009b). Genetic polymorphism in CYP2E1: Population distribution of CYP2E1 activity. J Toxicol Environ Health B Crit Rev, 12: 362-388.
- Walker K; et al (2009). Genetic polymorphism in N-acetyltransferase (NAT): population distribution of NAT1 and NAT2 activity. J Toxicol Environ Health, 12(5-6):440-72.