Epigenetics and chemical safety assessment.
Epigenetics, as it pertains to biology and toxicology, can be defined as heritable changes in gene expression that do not involve mutations and are propagated without continued stimulus. Although potentially reversible, these heritable changes may be classified as mitotic, meiotic, or transgenerational, implicating the wide-ranging impact of epigenetic control in cellular function. A number of biological responses have been classified as being caused by an "epigenetic alteration," sometimes based on sound scientific evidence and often in lieu of an identified genetic mutation. Complicating the understanding and interpretation of perceived epigenetic alterations is an incomplete understanding of the normal state and dynamic variation of the epigenome, which can differ widely between cell and tissue types and stage of development or age. This emerging field is likely to have a profound impact on the study and practice of toxicology in coming years. This document reviews the current state of the science in epigenetic modifications, techniques used to measure these changes, and evaluates the current toxicology testing battery with respect to strengths and potential weaknesses in the identification of epigenetics changes. In addition, case studies implicating transgenerational effects induced by diethylstilbestrol, vinclozolin, and bisphenol A were reviewed to illustrate the application of epigenetics in safety assessment and the strengths and limitations of the study designs. An assessment of toxicology tests currently used in safety evaluation revealed that these tests are expected to identify any potential adverse outcomes resulting from epigenetic changes. Furthermore, in order to increase our understanding of the science of epigenetics in toxicology, this review has revealed that a solid understanding of the biology and variation in the epigenome is essential to contextualize concerns about possible adverse health effects related to epigenetic changes. Finally, the fundamental principles guiding toxicology studies, including relevant doses, dose-rates, routes of exposure, and experimental models, need to be taken into consideration in the design and interpretation of studies within this emerging area of science.
LeBaron
Matthew J
MJ
Toxicology & Environmental Research & Consulting, The Dow Chemical Company, 1803 Building, Midland, MI 48674, USA.
Rasoulpour
Reza J
RJ
Toxicology & Environmental Research & Consulting, The Dow Chemical Company, 1803 Building, Midland, MI 48674, USA.
Klapacz
Joanna
J
Toxicology & Environmental Research & Consulting, The Dow Chemical Company, 1803 Building, Midland, MI 48674, USA.
Ellis-Hutchings
Robert G
RG
Toxicology & Environmental Research & Consulting, The Dow Chemical Company, 1803 Building, Midland, MI 48674, USA.
Hollnagel
Heli M
HM
Toxicology & Environmental Research & Consulting, The Dow Chemical Company, Horgen, Switzerland.
Gollapudi
B Bhaskar
BB
Toxicology & Environmental Research & Consulting, The Dow Chemical Company, 1803 Building, Midland, MI 48674, USA. Electronic address: bbgollapudi@dow.com.
D000818:Animals; D019175:DNA Methylation; D004285:Dogs; D064420:Drug-Related Side Effects and Adverse Reactions; D044127:Epigenesis, Genetic; D006801:Humans; D007109:Immunity / Q000187:drug effects; D051379:Mice; D023421:Models, Animal; D012098:Reproduction / Q000187:drug effects; D018570:Risk Assessment; D018675:Toxicity Tests; D014116:Toxicology