Occupational and Environmental Exposures

Patrice Sutton

Joanne L. Perron

Linda C. Giudice

Tracey J. Woodruff

INTRODUCTION

The fact that exposure to chemicals can harm human reproduction has been known since Roman times, when lead was first recognized to cause miscarriage and infertility in women and men.¹^,² Over the past 60 years, it has become clear that the placenta does not protect the fetus from damaging chemicals,³ that the fetus can be uniquely sensitive to chemical exposures,⁴^,⁵ and that intergenerational harm can result from in utero chemical exposures (Table 22.1).⁶^,⁷ These discoveries stemmed from exposure to drugs and higher levels of environmental chemical exposure than typically encountered by the general population. Until recently then, it was generally assumed that environmental exposures experienced by an average person living in the United States would be below levels of reproductive harm, that is, hazards that effect fertility, conception, pregnancy, and/or delivery.

A rapidly expanding body of scientific evidence has upended this assumption about the benign nature of “low-level” environmental exposures.⁷^,⁸ For example, studies have demonstrated that the levels of chemicals that an average person is exposed to can perturb biological processes, such as preventing genes from functioning normally and interfering with the hormonal regulation critical to healthy reproduction.⁹^,¹⁰ We now know that the human reproductive system is vulnerable to such biological perturbations, particularly when these changes occur during critical windows of development (Fig. 22.1). Even subtle perturbations caused by chemical exposures may lead to important functional deficits and increased risks of disease and disability in infants, children, and across the entire span of human life.¹¹, ¹², ¹³

ADVERSE TRENDS IN REPRODUCTIVE HEALTH

Scientific evidence of declining reproductive function and increasing rates of reproductive illnesses since the mid-20th century that suggest our reproductive health and, ultimately, our reproductive capacity are under strain.¹¹^,¹³, ¹⁴, ¹⁵ A spectrum of female and male reproductive disorders as well as poor birth outcomes and childhood disorders are increasing. (See Table 1 in reference 16 for a wide range of examples that exemplify adverse trends.)¹⁶ From 1990 to 2005, birth weight decreased among term births in the United States, and these declines were not explained by trends in maternal and neonatal characteristics, changes in obstetrical practices, or concurrent decreases in gestational length.¹⁷ There is increasing data that some aspects of human male reproductive health is declining and may be associated with exposure to a range of hormonally active toxicants.¹⁸, ¹⁹ Some of these effects include declines in serum testosterone levels over several decades, declines in sperm counts, and a shortened anogenital distance (seen after exposure to certain phthalates).¹⁹, ²⁰, ²¹ The evidence of impact from even lowlevel environmental exposures found in studies of laboratory animals and human populations is further amplified by signals from wildlife populations showing altered reproductive performance in annelids, mollusks, crustaceans, insects, fish, amphibians, and other mammals.²²^,²³

HUMAN EXPOSURE TO TOXIC ENVIRONMENTAL CHEMICALS

These trends in reproductive health changes have occurred in roughly the same time frame in which human exposure to both natural and synthetic chemicals has dramatically increased. Approximately 87,000 chemical substances are registered for use in U.S. commerce as of 2006, with about 3000 chemicals manufactured or imported in excess of 1 million pounds each,²⁴ and approximately 700 new industrial chemicals are introduced into commerce each year.²⁵ These chemicals are distributed throughout homes, workplaces, and communities and are found in food, water, air, and consumer products. All women (including pregnant women), men, children, and infants in the United States have measurable levels of multiple environmental contaminants in their body (Table 22.4).²⁶^,²⁷

The nature and extent of the relationship between these trends and environmental contaminants is rapidly unfolding. The strength of the evidence linking ubiquitous exposure to environmental contaminants to adverse health outcomes is sufficiently high that leading scientists and reproductive health and other clinical practitioners have called for timely action to prevent continued or future harm.¹²^,¹³^,¹⁶^,²⁸^,²⁹

TABLE 22.1 Examples of Human Evidence That Documents Key Principles in Reproductive Environmental Health

The placenta does not protect the fetus from damaging chemicals: Methylmercury

In the 1950s, methylmercury exposure in utero resulted in severe neonatal neurologic impairment in children after pregnant mothers consumed high levels of methylmercury in fish and shellfish contaminated from toxic industrial releases in Minamata, Japan. More recent evidence documents that developmental and cognitive effects can occur in children exposed prenatally to mercury at low doses that do not result in effects in the mother^{a, b, c} and that the adverse neurologic effects of methylmercury exposure may be delayed.^d,e As of 1992, there were 2252 officially recognized cases of Minamata disease.^f

The fetus can be uniquely sensitive to chemical exposures: Thalidomide

In the 1960s, thalidomide, a drug given to pregnant women for morning sickness, with no adverse maternal consequences, resulted in a high rate of congenital limb and gastrointestinal malformations when taken during days 28-42 postconception. It is estimated that more than 10,000 children in 46 countries where the drug had been approved were born with deformities as a consequence of their mothers using the drug during pregnancy.^g

Intergenerational harm can result from in utero chemical exposures: Diethylstilbestrol

Diethylstilbestrol (DES), which was prescribed in up to 10 million pregnancies from 1938 to 1971 to prevent miscarriage, was subsequently found to be a “transplacental carcinogen” causally linked to postpubertal benign and malignant reproductive tract abnormalities in the daughters and sons of DESexposed mothers. These adverse health impacts manifested only decades after exposure. Established health impacts of in utero DES exposure include vaginal clear cell adenocarcinoma, vaginal epithelial changes, reproductive tract abnormalities (e.g., gross anatomical changes of the cervix, T-shaped and hypoplastic uteri), ectopic pregnancies, miscarriages, and premature births, and infertility in females exposed in utero; reproductive tract abnormalities (e.g., epididymal cysts, hypoplastic testis, cryptorchidism) in males exposed in utero; and increased risk for breast cancer in women who took the drug while pregnant.^h Recent cohort studies indicate that women who were exposed to DES prenatally have an increased risk of breast cancer after age 40 years.ⁱ Animal data predict intergenerational impacts (i.e., among granddaughters of DES-exposed women) that is supported to date by limited human data.^j

^a^aGrandjean P, Weihe P, White RF, et al. Cognitive deficit in 7-year-old children with prenatal exposure to methylmercury. Neurotoxicol Teratol. 1997;19(6):417-428.

^b^bGrandjean P, Weihe P, White RF, et al. Cognitive performance of children prenatally exposed to “safe” levels of methylmercury. Environ Res. 1998;77(2):165-172.

^c^cGrandjean P, White RF, Nielsen A, et al. Methylmercury neurotoxicity in Amazonian children downstream from gold mining. Environ Health Perspect. 1999;107(7):587-591.

^d^dNational Research Council. Toxicological Effects of Methylmercury. Washington, DC: National Academy Press; 2000.

^e^eUS Environmental Protection Agency. Methylmercury (MeHg) (CASRN 22967-92-6). http://www.epa.gov/iris/subst/0073.htm. Accessed December 17, 2013.

^f^fHarada M. Minamata disease: methylmercury poisoning in Japan caused by environmental pollution. Crit Rev Toxicol. 1995;25(1):1-24.

^g^gUS Food and Drug Administration. This week in FDA history—July 15, 1962. http://www.fda.gov/AboutFDA/WhatWeDo/History/ThisWeek/ucm117836.htm. Accessed December 17, 2013.

^h^hNational Cancer Institute, National Institutes of Health. DES Research Update 1999: current knowledge, future directions, meeting summary. http://women.cancer.gov/planning/previous/DES/chapter1.html. Accessed December 17, 2013.

ⁱⁱPalmer JR, Wise LA, Hatch EE, et al. Prenatal diethylstilbestrol exposure and risk of breast cancer. Cancer Epidemiol Biomarkers Prev. 2006;15(8):1509-1514.

^j^jNewbold RR. Lessons learned from perinatal exposure to diethylstilbestrol. Toxicol Appl Pharmacol. 2004;199(2):142-150.

THE ROLE OF CLINICIANS IN PREVENTION

Clinicians caring for women of childbearing age are uniquely poised to prevent or identify possible harmful exposures to toxic environmental contaminants and must be able to respond to questions as well as advise patients about the (preventable) health impacts incurred by exposure to toxic substances.¹⁶ The embryo, fetus, and developing human are highly vulnerable to exposure to even small amounts of environmental toxicants,¹²^,¹³^,²⁸ due to their high metabolic rate, underdeveloped liver-detoxifying mechanisms, and immature
immune system and blood-brain barrier.³⁰ Reducing or eliminating exposure to environmental contaminants prior to conception is the most effective strategy for preventing adverse health consequences. Clinicians do not need to become experts in environmental and occupational health in order to fulfill this crucial role.

FIGURE 22.1 Windows of susceptibility. (Modified from Buck Louis GM, Gray LE Jr, Marcus M, et al. Environmental factors and puberty timing: expert panel research needs. Pediatrics. 2008;121[suppl 3]:S192-S207.)

This chapter presents an overview of the nature and extent of the scientific evidence linking exposures to environmental toxicants to reproductive and developmental health outcomes. It also outlines clinical management strategies for the general patient population and for the occupationally exposed patient, presents a case study for counseling patients about an environmental exposure, and provides other practical information for clinicians to assist them in addressing this important, and often overlooked, determinant of patient health.

DEFINITIONS

Reproductive Environmental Health

“Reproductive environmental health” addresses exposures to environmental contaminants (synthetic chemicals and metals), particularly during critical periods of development (such as prior to conception and during pregnancy), and their potential effects on all aspects of future reproductive health throughout the life course, including conception, fertility, pregnancy, child and adolescent development, and adult health.¹³ Reproductive environmental health is thus an important area of intervention for clinicians caring for patients with reproductive capacity.

Environmental Contaminants

Environmental contaminants include heavy metals and synthetic chemicals in air, water, soil, food, and consumer products, and found in the home, community, and workplace environment, such as pesticides, solvents, air pollution components, and persistent organic pollutants. Exposures causing reproductive harm may be physical forces (e.g., radiation, heat, excessive vibration), biological factors (e.g., viruses, parasites), or toxic agents. Toxicants may impact a fetus via direct maternal exposure during the pregnancy, or through effects that persist from previous maternal exposures (e.g., mobilization of stored toxicants from maternal fat or bone stores).

Critical and Sensitive Windows of Susceptibility

A critical window of susceptibility is a unique time period during development when exposures to environmental contaminants can disrupt or interfere with the physiology of a cell, tissue, or organ.¹² Exposures during this window may result in adverse, permanent effects that can have lifelong and even intergenerational impacts on health. Exposures during critical windows have specific effects on development; exposure to the same agent outside the critical window may incur different or no effects. In contrast, during a sensitive window of susceptibility, exposures may still affect development or result in eventual adult disease but with reduced magnitude compared with the effect of exposure during other time periods.³¹ Given that development continues after birth, critical and sensitive windows are seen during periconception, pregnancy, infancy, childhood, puberty, pregnancy, and lactation (see Fig. 22.1).

Stage-specific effects of ethylene oxide used for sterilizing medical supplies and in manufacturing are illustrative of how the timing of exposure matters to whether and what adverse health outcome(s) arise. Ethylene oxide can induce skeletal effects when administered to mice at the zygote stage of development—long before skeletogenesis begins.³²^,³³ The spectrum of skeletal effects observed after exposure at the zygote stage differs from those observed after exposure during organogenesis.

Recent research into the mechanisms of toxicity of the pesticide chlorpyrifos, which can inhibit cholinesterase inhibitor and thus is neurotoxic, is also illustrative of this new paradigm. The conventional view of neurotoxicity from chlorpyrifos involves the metabolism of the molecule by the liver to the chlorpyrifos oxon, which causes an irreversible inhibition of acetylcholinesterase. However, animal studies by Slotkin and colleagues demonstrated that effects of chlorpyrifos on the developing brain are subtle, widespread, and can occur below the threshold for any signs of exposure, and even without any detectable cholinesterase inhibition.³⁴^,³⁵ Moreover, these studies have shown that chlorpyrifos disrupts rat brain development through a variety of cellular and molecular mechanisms, with both the mechanism and the outcome changing with the progression of cell differentiation.

The U.S. Environmental Protection Agency (USEPA) has not yet incorporated the implications of the critical nature of the timing of exposure into pesticide toxicity testing protocols. Data collected from manufacturers, the main source of USEPA data, often overlooks developmental, morphologic, and functional damage of fetal origin.³⁶

Developmental Basis of Disease/Dysfunction

The Developmental Basis of Adult Disease/Dysfunction describes links between the in utero environment, the external environment, an individual’s genes, and the propensity to develop disease or dysfunction later in life.²⁸ The central nervous system, the cardiovascular system, the endocrine system, and the immune system appear to be particularly vulnerable to adverse effects during early development, and specific diseases, such as particular cancer forms, may well be initiated before birth or during early postnatal life.¹²

Perinatal factors and their influences on the development of chronic adult disease was first described in the field of nutrition³⁸ with the evidence base independently evolving in the field of developmental toxicology.³⁰
Animal studies clearly show that the in utero and neonatal developmental periods represent “critical windows” for nutrition and environmental exposures to impact later development.⁴⁰ Other important features about the developmental origins of disease and dysfunction paradigm are:

The initiating in utero environmental insult can act alone or in concert with other environmental stressors;
There is a range of potential effects and latencies (including the potential to affect future generations);
Aberrant developmental programming can permanently alter gland, organ, or system potential;
Altered gene expression or altered protein regulation likely play a role in the toxicant or nutritionally induced pathogenic responses.³⁹^,⁴⁰

One example of the developmental origins of disease/dysfunction paradigm of practical import to the practicing clinician is the hypothesis that in addition to the impact of maternal nutrition on fetal growth, environmental endocrine disrupting chemicals can act as “obesogens” that can permanently derange developing regulatory systems required for body weight homeostasis.⁴⁰^,⁴¹ Paradoxically, our food system contributes to virtually all of the fetal and developmental chemical exposures linked to obesity that were cited in the May 2010 White House Task Force on Childhood Obesity Report to the President,⁴² including Bisphenol-A, perfluorooctanoate (PFOA), phthalates, fructose, and certain organophosphate pesticides.

PATIENT EXPOSURE TO ENVIRONMENTAL CONTAMINANTS

Chemical Agents

Synthetic chemicals and metals linked to reproductive, fertility, and/or developmental health effects are distributed throughout homes, workplaces, and communities, and contaminate food, water, air, and consumer products.⁴³ For example, certain chemicals in commonly used plastics⁴⁴ and persistent pesticides⁴⁵^,⁴⁶ share the ability to alter the endocrine, neurologic, and/or other biological systems. Plastics and pesticides are only two of the many chemical exposures encountered in daily life. Over 10,000 ingredients are used in personal care products; nearly 90% of these ingredients have not been evaluated for safety by any publicly accountable institution. People apply an average of 126 unique ingredients on their skin daily.⁴⁷ Table 22.2 lists examples of common contaminants, sources, and exposure circumstances linked to adverse reproductive, fertility, and/or developmental health outcomes.

Population-based studies conducted by the U.S. Centers for Disease Control and Prevention (CDC) demonstrate ubiquitous exposure to many chemicals found in homes, communities, and workplaces that can disrupt the normal functioning of hormones and cause other toxicities.²⁶^,²⁷ An analysis of CDC population-based biomonitoring data among pregnant women in the United States found virtually all pregnant women have body burdens of lead, mercury, toluene, pesticides, perchlorate, BPA, phthalates, perfluorochemicals (PFCs), polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDEs) (Table 22.3). Analysis of second-trimester amniotic fluid samples from 51 women found the presence of at least one environmental contaminant.⁴⁸ In some cases, such as for mercury, fetal exposures to environmental contaminants may be higher than maternal.⁴⁹, ⁵⁰, ⁵¹ A 2013 report by CDC found mercury was present in 83% of U.S. women of childbearing age.⁵²

Physical and Biological Agents

Although the focus of this chapter is occupational and environmental exposure to chemical agents, the practicing clinician needs to be aware that patient exposure to physical and biological agents can also impact health, including reproductive health. For example, shift work, that is, exposure to “light-at-night” involving circadian disruption, is associated with breast cancer in human studies, and, on the basis of human and animal evidence, has recently been classified by a Working Group of the International Agency for Research on Cancer as “probably carcinogenic to humans” (Group 2A).⁵³ Exposure to physical hazards such as ionizing radiation and biological hazards such as blood-borne pathogens are also of relevance to reproductive health practitioners, particularly among those with patients working in the health care sector.

THE EVIDENCE STREAM SUPPORTING CLINICAL DECISION MAKING RELATED TO ENVIRONMENTAL AND OCCUPATIONAL EXPOSURES

The evidence stream and decision context in environmental health sciences is quite different from that of clinical science and practice (Fig. 22.2).⁵⁴ Clinicians cannot assume as they do with pharmaceuticals that adequate in vitro and in vivo testing has been undertaken and considered by regulatory agencies before widespread human exposure to environmental contaminants occurs. Just because a product is readily available on the shelf at the store is no assurance that it is nontoxic. The vast majority of chemicals in commerce have entered the marketplace without comprehensive and standardized information on their reproductive or other chronic toxicities.⁵⁵ The inadequacies of the current regulatory framework are receiving increased attentions, and in 2009, the USEPA established “Essential Principles for Reform of Chemicals Management Legislation” to help inform legislative efforts now underway to reauthorize and significantly strengthen the effectiveness of chemical regulation.⁵⁵

TABLE 22.2 Selected Examples of Contaminants Linked to Reproductive, Fertility, or Developmental Problems

Types of Contaminants and Examples	Sources and Exposure Circumstances
Metals
Mercury	Occurs from energy production emissions and naturally. According to the U.S. EPA, coal-fired power plants are the largest current sources of mercury emissions in the country. Enters the aquatic food chain through a complex system. Primary exposure by consumption of contaminated seafood.
Lead	Occupational exposure occurs in battery manufacturing/recycling, smelting, car repair, welding, soldering, firearm cleaning/shooting, stained glass ornament/jewelry making; nonoccupational exposure occurs in older homes where lead-based paints were used, in or on some toys/children’s jewelry, water pipes, imported ceramics/pottery, herbal remedies, traditional cosmetics, hair dyes, contaminated soil, toys, costume jewelry.
Organic compounds
Solvents	Used for cleaning, degreasing, embalming, refinishing and paint systems in a wide range of industries. Found in automotive products, degreasers, thinners, preservers, varnish and spot removers, pesticides (inert component), and nail polish.
Ethylene oxide	Occupational exposure to workers sterilizing medical supplies or engaged in manufacturing.
Pentachlorophenol	Wood preservative for utility poles, railroad ties, wharf pilings; formerly a multiuse pesticide. Found in soil, water, food, and breast milk.
Bisphenol-A (BPA)	Chemical intermediate for polycarbonate plastic and resins. Found in consumer products and packaging. Exposure through inhalation, ingestion, and dermal absorption.
Polychlorinated biphenyls (PCBs)	Used as industrial insulators and lubricants. Banned in the 1970s, but persistent in the aquatic and terrestrial food chains resulting in exposure by ingestion.
Dioxins	Dioxins and furans are multiple toxic chemicals formed by trash and waste incineration involving chlorine and, as categorized as a persistent organic pollutants (POPs), pervasive chemicals which bioconcentrate as they move up the food chain. Found in dairy products, meat, fish and shellfish.
Perfluorochemicals (PFCs)	PFCs are widely used man-made organofluorine compounds with many diverse industrial and consumer product applications. Examples are perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA), which are used in the manufacture of nonstick Teflon and other trademark cookware products and in food-contact packaging to provide grease, oil, and water resistance to plates, food containers, bags, and wraps that come into contact with food. Persist in the environment. Occupational exposure to workers and general population exposure by inhalation, ingestion, and dermal contact.
Polybrominated diphenyl ethers (PBDEs)	Flame retardants that persist and bioaccumulate in the environment. Found in furniture, textiles, carpeting, electronic, and plastics.
Di-(2 ethylhexyl) phthalate (DEHP), diethyl phthalate (DEP), di-n-butyl phthalate (DBP)	Synthetically derived; phthalates are used in a variety of consumer goods such as medical devices, cleaning and building materials, personal care products, cosmetics, pharmaceuticals, food processing, and toys. Exposure occurs through ingestion, inhalation, and dermal absorption.
Pesticides	Applied in large quantities in agricultural, community, and household settings. In 2001, over 1.2 billion pounds of pesticide active ingredients were used in the United States. Pesticides can be ingested, inhaled, and absorbed by the skin. The pathways of pesticide exposure include food, water, air, dust, and soil.
Chlorpyrifos	Organophosphate pesticide used in agricultural production and for home pest control (home uses are now restricted).
Dichlorodiphenyltrichloroethane (DDT)^*	Organochlorine insecticide, banned in the United States in the 1970s, is still used for malaria control overseas. Present in the food chain.
Air contaminants
Environmental tobacco smoke (ETS) Particulate matter (PM), ozone, lead Glycol ethers	Burning of tobacco products. Exposure by inhalation from active or passive smoking. Sources include combustion of wood and fossil fuels, and industrial production. Exposure by inhalation. Used in enamels, paints, varnishes, stains electronics, and cosmetics. Occupational and general population exposure by inhalation, ingestion, and dermal contact.
Note: Contaminants in italics are persistent and/or bioaccumulative.
Adapted from Fox MA. Environmental contaminants and exposure. In: Woodruff TJ, Janssen JS, Guillette LJ Jr, et al, eds. Environmental Impacts on Reproductive Health and Fertility. New York: Cambridge University Press; 2010.

Moreover, regulatory and medical ethical requirements dictate that human exposure to pharmaceuticals does not occur in the absence of some potential benefit greater than the known risks. The “gold standard” for informing clinical risk-benefit decisions about medical interventions is a well-conducted randomized controlled trial. There is no comprehensive comparable weighing of health benefits and risks in the environmental arena. Because of the shortcomings of the United States’ current regulatory structure for governing manufactured chemicals population, exposure to exogenous substances in the environment typically occurs prior to regulatory scrutiny of a compound and in the absence of risk-benefit analyses. The benefits of environmental chemicals are largely unrelated to patient health, and exposures are generally unintentional and highly variable. Randomized controlled trials on environmental contaminants are virtually precluded from the evidence stream
due to ethical considerations. Therefore, when making decisions about patient exposure to environmental and occupational exposure to chemicals, clinicians must rely on in vitro and in vivo studies for early warnings of adverse effects and human observational studies to assess the nature and extent of the damage.

TABLE 22.3 Percentage of U.S. Pregnant Women With Metals and Synthetic Chemicals Measured in Their Body^*

Chemical Analyte	Percentage of U.S. Pregnant Women With Detectable Levels of the Analyte	Chemical Analyte	Percentage of U.S. Pregnant Women With Detectable Levels of the Analyte
Metals (blood; mcg/L) (N = 253)		Organochlorine (OC) pesticides (serum; ng/g lipid) (N = 71)
Cadmium	66	DDT	62
Lead	94	DDE	100
Mercury (total)	89	Hexachlorobenzene	100
VOCs (blood; mcg/L) (N = 89)		Organophosphate (OP) insecticide metabolites (urine; mcg/L) (N = 89)
Benzene	38	Dimethylphosphate (DMP)	44
1,4-Dichlorobenzene	40	Diethylphosphate (DEP)	33
MTBE (N = 85)	86	Dimethylthiophosphate (DMPT)	83
Toluene (N = 90)	94	Diethylthiophosphate (DEPT)	57
		Dimethyldithiophosphate (DMDTP)	56
PFCs (serum; mcg/L) (N = 76)
PFOA	99	Environmental phenols (urine; mcg/L) (N = 86)
PFOS	99	Bisphenol-A	96
PBDEs (serum; ng/g lipid) (N = 75)		Triclosan	87
PBDE-47	99	Benzophenone-3	100
PBDE-99	87	Phthalates (urine; mcg/L) (N = 91)
PBDE-100	99	Mono-n-butyl phthalate (MnBP)	99
PBDE-153	100	Mono-ethyl phthalate (MEP)	100
PCBs (serum; ng/g lipid) (N = 75)		Mono-benzyl phthalate (MBzP)	100
PCB-118	100	Mono-isobutyl phthalate (MiBP)	99
PCB-138 & 158	100	Perchlorate (urine; mcg/L) (N = 89)
PCB-153	100	Perchlorate	100
PCB-180	96
DDT, dichlorodiphenyltrichyloroethane; DDE, dichlorodiphenyl dichloroethylene; VOCs, volatile organic compounds; MTBE, methyl-tert-butyl ether; PFC, perfluorochemical; PFOA, perfluoroctanoate; PFOS, perfluorooctane sulfonate; PBDE, polybrominated diphenyl ether; PCB, polychlorinated biphenyl.
^*Based on analysis of representative sample of U.S. population by the U.S. Centers for Disease Control and Prevention, National Health and Nutrition Examination Survey 2003-2004.
From Woodruff TJ, Zota A, Swartz JM. Environmental chemicals in pregnant women in the United States: NHANES 2003-2004. Environ Health Perspect. 2011;119(6):878-885.

The reliability of experimental animal data for reproductive and developmental health has been well established through multiple studies of concordance between animals and humans after exposure to a variety of chemical agents.⁵⁶, ⁵⁷, ⁵⁸, ⁵⁹, ⁶⁰ Presently, there is no example of a chemical agent that has adversely affected human reproduction or development but has not caused the same or similar adverse effects in animal models.⁵⁸ The National Academy of Sciences (NAS) has recognized the importance of animal data in identifying potential developmental risks. According to the NAS, studies of comparison between developmental effects in animals and humans find that “there is concordance of developmental effects between animals and humans and that humans are as sensitive or more sensitive than the most sensitive animal species.”³³ Biological function is conserved across animal species. Therefore, signals obtained from wildlife studies further strengthen the evidence seen in laboratory animals and human cell cultures.⁶¹

Human observational studies of environmental chemicals provide the most direct evidence of the relationship between exposure and increased risk of adverse health outcomes and are often the basis of regulatory and policy decision making. However, human epidemiologic studies require that we wait for people to develop clearly identified diseases from exposure and thus are not an optimal approach to clinical decision making. Whereas an experimental animal carcinogenic study typically lasts 2 years, it can take 20 years to get a result from a comparable human study.⁶² For all of these reasons, the use of animal data and other non-human model systems is fundamental to timely prevention of adverse health outcomes in clinical decision making.

MECHANISMS OF ACTION

Epigenetic Mechanisms

The term “epigenetics” includes any process that alters gene activity and expression without mutating the DNA sequence and leads to modifications that can be transmitted
to daughter cells.⁶³ Environmental modifications of gene expression can affect embryonic imprinting, cellular differentiation, and phenotypic expression.⁶⁴ The most common epigenomic alterations are methylation of the DNA at cytosine with subsequent gene silencing or modification of the DNA histone support, which affects chromatin folding and attachment. Tight folding inhibits gene expression and lithe folding allows gene manifestation.⁶⁴

FIGURE 22.2 Comparison of streams of evidence in clinical and environmental health sciences.

Illustrative of epigenetic mechanisms, in 2005, studies on laboratory animals began to establish a novel mechanism of action not previously appreciated on how pesticides and other environmental contaminants could act on a gestating mother to influence her grandchildren and subsequent generations.⁶⁵ Studies of male rats exposed to the fungicide vinclozolin demonstrated that epigenetic damage may be passed on to future generations. More recently, scientists have shown that female rats exposed to vinclozolin during a specific period of pregnancy exhibit a transgenerational increase in pregnancy abnormalities and female adult onset disease states.⁶⁶ These effects occurred after large doses were given and are not indicative of average occupational exposure to this pesticide. However, this study highlights the importance of performing transgenerational studies when evaluating the toxicology of environmental compounds.

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