This document provides a summary and critique of literature surrounding endocrine disruptor compounds (EDCs). It first discusses the mechanisms by which EDCs can interfere with hormone function and their presence in various products. It then summarizes two opposing literature reviews on the effects of low doses of bisphenol A (BPA). One review by Michael Kamrin found inconsistencies in studies supporting low-dose effects, while another by vom Saal and Hughes provided evidence that low doses of BPA can harm health. The author agrees more with the latter review and critiques Kamrin's potential biases. Overall policies aim to reduce BPA exposure, and more research on EDC mechanisms and epidemiological studies is recommended.

1. Tina Safavie
Science, Technology, International Affairs
Georgetown University
A Critical Assessment of Literature Surrounding Endocrine Disruptor Compounds
With the advent of better detection technologies, the scientific community has recently become
cognizant of the presence of chemicals known as endocrine disruptor compounds within our
environment. These compounds are identified by the National Institute of Environmental Health
Sciences (NIEHS) as naturally occurring or synthetic chemicals that mimic or interfere with the function
of hormones in the body. In order to critically assess this emerging threat, my paper explores the
scientific mechanisms behind these substances. Subsequently, I assess the competing views of existing
skeptics and optimists in regards to the low-dose effects of bisphenol A (BPA) on human models and
then critique the literature of the opposing parties.
The human endocrine system, working synergistically with other organ systems, is vital for our
survival and function as human beings. Complete with hundreds of hormones and an extensive
transportation network, the endocrine system is responsible for coordinating numerous bodily functions
such as reproduction, growth, and homeostasis. Since hormones interact with cell receptors at parts-
per-billion and part-per-trillion levels, their release and subsequent distribution throughout the body is
tightly regulated. Consequently, small disturbances in blood hormone levels have drastic biological
effects on normal growth and development. The delicate nature of this hormonal signaling system thus
illustrates reasons for the potential lethality of endocrine disruptor chemicals. Further, this sensitivity
also highlights the reasoning behind concerns over the presence of endocrine disruptor chemicals in our
environment, even at low-dose levels.
Endocrine disruptor chemicals (EDCs), also termed endocrine modulators, are naturally-occurring or
synthetic substances found within our environment. These compounds are present in various products,

2. including plastic bottles and containers, detergents, flame retardants, pesticides, and beauty supplies.
Interestingly, endocrine disruptors can also be found in various food and water sources. Researchers
funded by National Institute of Environmental Health Sciences (NIEHS) have identified three primary
mechanisms for damage incurred by endocrine disruptors (figure 1) (NIEHS 2010). First, endocrine
disruptors can naturally mimic hormones to produce overstimulation of respective responses. Second,
endocrine disruptors can also bind cellular receptors and prevent endogenous hormones from binding
their targets, inhibiting normal responses. Lastly, endocrine receptors potentially block mechanisms
responsible for hormone and receptor production (NIEHS 2010).
Research studies conducted on experimental animals and wildlife ascertains the negative
consequences of manipulating endocrine responses in the manners highlighted above. For example,
studies indicate that animals exposed to EDCs have increased incidence rates of prostate, breast and
ovarian cancers, autoimmune and immune diseases, as well as some neurodegenerative diseases. EDCs
have also been found to cause a vast array of both male and female reproductive health and fertility
issues, including decreased fertility, reproductive organ abnormalities, and early onset puberty. Along
with disruption of mechanisms dependent on hormones, research suggests that endocrine disruptors
have the greatest negative influence in utero during heightened periods of development (NIEHS 2010).
The National Toxicology Program Center for the Evaluation of Risks to Human Reproduction has
identified a wide range of chemicals that cause endocrine disruption, including di (2-ethylhexyl)
phthalate (DEHP), Bisphenol A (BPA), and polychlorinated biphenyls (PCBs). Specifically of interest to this
paper is the EDC bisphenol A, a compound typically used in the development of polycarbonate plastics
and epoxy resins (NTP 2008). Due to the BPA compound’s susceptibility to hydrolysis upon heating,
humans are frequently exposed to this chemical within the environment. In fact, the Centers for Disease
Control & Prevention (CDC) reports that 95% of urine samples collected from Americans throughout the
nation have detectable levels of BPA, ranging from levels of .4 ppb to 8 ppb. After careful investigation,

3. the NTP expresses “some concern for effects on the brain, behavior and prostate gland in fetuses,
infants, and children at current human exposures to BPA,” (NTP 2008).
It has been frequently hypothesized and widely accepted among scientists that exposure to low-
doses of endocrine disruptor chemicals have severe health implications. These adverse health effects
include, but are not limited to, the increased incidence of certain cancers, neurodegenerative diseases,
and fertility issues. Although there is extensive data supporting this particular hypothesis, other
scientists believe there is not enough compelling evidence suggestive of the fact that humans are at risk
from chemicals purported to exhibit low dose effects. Their skeptical views arise from observations that
there are inconsistencies with the experimental design and inappropriate interpretations, rendering the
data obsolete. In other words, though the opposing sides agree on adverse effects resulting from high
dose EDC exposure, they diverge on their interpretation of the results set forth by studies on low dose
effects of endocrine disruptor chemicals. To further elucidate this controversial debate within the
scientific community, I chose to assess the literature reviews published by the Center for Integrative
Toxicology at Michigan State University and the Journal of Environmental Health Perspectives.
In his publication, “Low Dose” Hypothesis: Validity and Implications for Human Risk’, Dr. Michael
Kamrin critically reviewed existing literature supporting the hypothesis that low-dose exposure to
bisphenol-A resulted in adverse health effects. Kamrin evaluated these studies for their fulfillment of
basic scientific precepts, including data reproducibility, relevancy to human subjects, and use of proper
controls (Kamrin 2004). The degree to which these criteria are met [or unmet] lay the foundation for
Kamrin’s conclusion that “low-dose” effects of BPA have yet to be established. For instance, Kamrin
evaluates studies involving whole animal (in vivo) experiments for their fulfillment of scientific precepts.
Here, he ascertains that the end points assessed in “low dose” animal studies, such as prostate weight
and mammary gland morphology, are not measures of reproductive or developmental functioning, but
rather biochemical or morphological in nature. Therefore, these effects are not necessarily indicative of

4. the adverse impact of EDCs on functioning (Kamrin 2004). Another criticism set forth by Kamrin relates
to his assessment of environmentally relevant BPA exposure levels. He argues that all reported low dose
effects of BPA result from exposures well above normal ranges in non-environmental exposure
mechanisms, such as subcutaneous injections and implantations. Since humans are typically exposed to
EDCs at significantly lower levels, Kamrin claims these studies are inappropriate for determining the
effects of BPA on health. Ultimately, this comprehensive review ascertains that results supporting the
low-dose hypothesis reflect experimental inconsistencies and misinterpretation of results.
Michael Kamrin’s comprehensive review ‘“Low Dose” Hypothesis: Validity and Implications for
Human Risk,’’ was an interesting assessment of the existing literature on the effects of endocrine
disruptor chemicals. Upon reading this study, I agreed with various points highlighted by Kamrin. For
instance, I agreed with Kamrin on the importance of evaluating the low dose hypothesis by applying
basic precepts of scientific validity; especially on his criterion of pattern emergence, reproducibility, and
necessity for appropriate and relevant experimental conditions. His claims suggesting that humans are
exposed to significantly lower levels of BPA than levels reported to cause adverse effects is also worth
agreement. However, after repeatedly encountering Kamrin’s superficial dissection of each experiment
cited in support for the low dose hypothesis, I deduced that he was inventing flaws within the context of
his personal precepts to further his conclusions. To gain a better understanding for Kamrin’s motivation
in publishing this literature review, I examined his background and professional affiliations. Interestingly,
Kamrin sits on the Board of Scientific and Policy Advisors for the American Council on Science and
Health, which is funded by Dow Chemical. This relationship with Dow Chemical casts doubt on the
scientific integrity of his publication as he may have financial incentive to mask the harmful effects of
synthetic compounds.
Frederick S. vom Saal and Claude Hughes published a literature review entitled “An Extensive
New Literature Concerning Low-Dose Effects of Bisphenol A Shows the Need for a New Risk Assessment.”

5. Similar to Kamrin, these scientists also conducted a review of the existing literature reporting harmful
effects of low dose exposure to bisphenol A. Whereas Kamrin attributed the reports on adverse effects
of low dose BPA to experimental design flaws and study inadequacies, these individuals interpreted the
results in a completely different manner. For example, vom Saal and Hughes used data from their
literature review to support the hypothesis that low dose exposures to EDCs are harmful to human
health. Interestingly, along with Kamrin, vom Saal and Hughes also addressed experimental design flaws
within existing EDCs literature. Instead of using these flaws to delegitimize the data, however, they cited
these studies to demonstrate the need for better practices and standardization under the umbrella of
EDC research (vom Saal et al. 2005). The researchers then cited additional studies to support the claim
that low levels of BPA still poses a threat to human health. For example, vom Saal and Hughes
highlighted studies indicating that altered immune function occurred at low doses of BPA between 2.5
and 30 g/kg/day. They also described studies demonstrating that in response to leached BPA from
polycarbonate drinking bottles at doses between 15 and 70 g/kg/day, there was significant disruption
of chromosome alignment during meiosis within developing oocytes. Additionally, the scientists
included assessment of studies indicating that with increasing BPA exposure, mice and rats developed
hyperactivity, aggressiveness, and altered reactivity to painful and fear-provoking stimuli. Further,
developmental exposure to BPA at 30 g/kg/day induced structural brain changes which reversed normal
sex differentiation and eliminated gender specific behavior. Directly contrasting with Kamrin, vom Saal
and Hughes found convincing evidence that biologically active levels of BPA in human blood are well
above the amount that has been determined to cause tissue damage (Saal et al. 2005). In summary,
this comprehensive literature review supports the scientific consensus that BPA causes adverse effects
in animals at doses well below the current reference dose. I found that the publication “An Extensive
New Literature Concerning Low-Dose Effects of Bisphenol A Shows the Need for a New Risk Assessment,”
to be highly informative and very well written. Not only do Saal and Hughes approach this topic in an

6. objective manner, but they also clarify experimental design flaws within existing literature while offering
mechanisms to remedy the problem.
In light of this assessment, I find vom Saal and Hughes comprehensive literature review on low
dose effects of BPA more convincing and reliable than that of Kamrin. I agree with vom Saal and Hughes’
assertion that low dose exposure to BPA poses a threat to health primarily due to their inclusion of
literature that elucidates the mechanistic pathways of EDCs responsible for adverse health effects. For
example, they specifically cite a comprehensive document published by the Endocrine Disruptors Group
which contains information on the mechanisms of action, pharmacokinetics and sources of exposure.
The fact that vom Saal and Hughes are able to provide scientific evidence for the negative effects of BPA
lends support to the notion that these claims are backed by strong scientific reasoning. Although
Kamrin provides a very thorough and extensive assessment of existing literature on low dose effects, I
do not find his conclusion convincing for a multitude of reasons. For instance, I think that it is
inappropriate for Kamrin to assert the dozens of scientists he critiqued did not follow basic scientific
precepts of reproducibility, consistency and proper experimental design. The very fact that these
scientists have been published in reputable journals such as Science and Nature negates Kamrin’s claims
of their negligence. Additionally, Kamrin’s insistence that reproducibility is equivalent to the exact same
study results every time is unrealistic and not representative of what is required for reproducibility
within accepted scientific paradigms (Vandenberg 2012). Further, within the field of epidemiology and
according to Bradford-Hill criteria, one single negative result does not negate all other studies showing
adverse effects (Vandenberg 2012). Although not a technical point, I find Kamrin’s association with Dow
Chemical highly compromising of his conclusions insisting that low doses of EDCs are not harmful to
human health.
In order to make policy recommendations regarding the levels of BPA in the environment, is it
important to understand the data set forth by the National Toxicology Program. According to the NTP,

7. there are five levels of concern from lowest to highest relating to the possible effects of current
exposures to BPA on human growth and functioning (figure 2). With this in mind, there are several
policy recommendations already in place by the Food and Drug Administration (FDA). For example, the
FDA has established regulations that seek to reduce human BPA expose by supporting industry’s efforts
to eliminate BPA from baby bottles, facilitating the development of BPA alternatives, and supporting
initiatives to reduce or minimize BPA in other products (FDA 2013). In order to allow for better decisions
in the future, I recommend much needed research and information. For instance, it is absolutely critical
that researchers collaborate extensively to develop new tools and techniques for elucidating
mechanisms of endocrine disruptor chemicals function. These include creating high throughput assays,
biomarkers or technology with enhanced ability to detect miniscule levels of EDCs in the environment.
To learn more about the effect of EDCs on certain populations, it would be worthwhile to expand
epidemiological studies to include more individuals, international participants, and various other
demographics.

8. Citations & Figures
Figure 1:
Figure 2:

9. Citations:
vom Saal FS, Hughes C (2005) Environ Health Perspect. An extensive new literature concerning low-dose
effects of bisphenol A shows the need for a new risk assessment. 113:926 – 933.
Vandenberg LN, Colborn T, Hayes TB, Heindel JJ, Jacobs DR, Jr, Lee DH, et al. Hormones and endocrine-
disrupting chemicals: low-dose effects and nonmonotonic dose responses. Endocr Rev. 2012;33:378–
455.
Kamrin, Michael. "The "Low Dose" Hypothesis: Validity and Implications for Human Risk." International
Journal of Toxicology 26.1 (2007): 13-23. Web.
http://www.niehs.nih.gov/health/topics/agents/endocrine/