Lessons from A Toxicology Detective Story: Use Caution with Controls

This article was originally posted on the Massive Science Consortium website, with the title “An Unexplained Result Shows Why Studying the Effects of Chemicals is so Tricky

Toxicologists are no strangers to mysteries. In fact, understanding unexpected results caused by unintentional chemical contamination in the laboratory has a storied history in the environmental health field.

In the late 1980’s, researchers at Tufts University accidentally discovered that certain plastic components caused their estrogen-responsive cells to grow uncontrollably. Their findings spurred extensive work on endocrine disrupting chemicals (EDCs), which can interfere with normal hormonal activity in the body. Bisphenol-A (BPA), found in many plastic products, is a common example of an EDC.

Following in this tradition, researchers at the University of Massachusetts (UMass) Amherst recently conducted some important toxicology detective work after they noticed that mammary glands of adult male mice raised in a commercial laboratory (that supplies mice for scientists) were larger and more developed than the mammary glands of the same type of mice raised in their own laboratory.

Scientists use rodent mammary glands as models of human breasts, which allow them to better understand growth and development as well as risk factors and treatments for diseases like breast cancer. Toxicologists have paid particular attention to how mammary glands change after exposure to EDCs, since the chemicals can interfere with hormonal activity and mammary glands are especially responsive to hormonal signals.

So, when the UMass Amherst researchers noticed a difference in the mammary glands between the two groups of theoretically similar mice, it set off some alarm bells. Could an unidentified EDC exposure in the commercial lab be the culprit? And if so, could this potential EDC exposure impact the ability of scientists and policy-makers to draw conclusions from toxicological experiments?

Comparing Gland Growth

To find out, the researchers carefully compared the mammary glands and blood hormones between the two groups of mice. One group was ordered directly from a commercial supplier. The other group was ordered from the same commercial supplier and then bred for two generations to produce offspring that were raised in their own lab under controlled conditions to minimize exposure to EDCs.

The findings supported their preliminary observations: the mammary glands in the male mice raised in the commercial lab were larger and more developed than those of male mice raised in their own lab. The researchers noted that the commercially-raised mouse mammary glands actually mirrored those of mice from different experiments that had been intentionally exposed to BPA during early development.

By contrast, female mice had smaller and less developed mammary glands at puberty. While this difference in response may at first seem counter-intuitive, endocrine disruptors are complicated. Because they interfere with hormones, which are gender-specific, EDCs have the potential to affect males and females in different ways.

Contemplating the Culprit

Although the researchers found differences between the two sets of mice, they didn’t immediately know why. A simple explanation would have been that different amounts of circulating hormones at the time they examined the mice might have influenced their body composition. Yet, they detected no significant differences in estrogen, the primary hormone that drives mammary gland development, between the two groups.

It is also unlikely that genetic differences could have contributed to the distinct mammary gland growth, given that the non-commercially raised animals were actually only two generations removed from the original commercial strain. Such drastic genetic changes do not usually occur over such short cycles.

Therefore, the researchers hypothesized that the difference was more likely due to the effects of EDC exposures during their early life in the commercial laboratory. (However, they were not able to confirm this theory through specific tests.) Exposures to EDCs, among other chemicals, during sensitive windows of development in early life have the potential to cause long-lasting changes, including in the mammary gland.

Considering the Consequences

These findings, which suggest that animals raised in commercial labs may be exposed to EDCs, could impact how we interpret toxicological studies.

One main reason is what researchers call the “two-hit” model, which suggests that an exposure in early life makes an individual more sensitive to the effects of a second exposure later in life. In this context, early exposures to EDCs might prime laboratory animals for more pronounced responses when treated with a test chemical in an experiment later in life. In other words, some laboratory experiments may be erroneously linking the test chemical to an outcome that is actually due to a combination of the test chemical and being exposed to EDCs earlier in life.

This study only evaluated animals from one commercial lab, and conditions may differ in other labs. The possibility that animals could be subject to different unintentional exposures may affect our ability to compare studies and pool data from diverse labs to make science-based policies. This issue may also partially explain why research and policy on EDCs has been so highly controversial, with distinct labs generating very different results about the same chemicals.

These differences also have implications for a controversial practice in the field of toxicology: the use of “historical controls.” Sometimes, scientists compare the changes in treated animals from one study to a database of untreated animals from a collection of previous studies. This practice can provide researchers with a better sense of whether the treated animals they are studying are truly different from normal. Yet, this study suggests that control animals raised in some laboratories may be exposed to EDCs, and therefore it would not be appropriate to compare them to treated animals raised in different environments. The presence of too many differing variables would make it difficult to make an accurate comparison.

Taken together, these findings suggest that both scientists and the public should be cautious when interpreting certain studies. While the researchers did not conclusively confirm the linkage to early life EDC exposure, this highly likely explanation illustrates that, at least in some cases, there may be factors behind the scenes that could be influencing the results of toxicology experiments.

How should the scientific community address the implications of this study? While researchers could try to mitigate the impact of these exposures on their subsequent toxicological experiments by screening animals prior to beginning their work, a better approach would be to improve handling of animals in commercial facilities through strict standards. Exposures to EDCs, among other chemicals, should be minimized. If such exposures continue, it may be hard to trust the results of these toxicological studies, which could impede the development of appropriate, evidence-based environmental health policies and protections for the population.

Developing Data on the “Developmental Origins of Health and Disease”

The Developmental Origins of Health and Disease (DOHaD) paradigm suggests that there are specific windows of development that are highly susceptible to disruption from environmental exposures and that these early life exposures can lead to adverse outcomes later in life. The British epidemiologist David Barker is credited with pioneering this field in the 1980’s, with his research on the link between prenatal nutrition and adult coronary heart disease.

Last month, researchers published a review of the environmental epidemiological literature on DOHaD in a special “Developmental Origins of Disease” issue of Reproductive Toxicology. This review paper, which summarizes 425 articles published between 1988-2014, provides a helpful overview of the state of the science and identifies key areas for future study.

Chemical Culprits

Across these hundreds of publications, which chemicals emerged as the most commonly examined culprits?

Figure 3 from their review, below, displays this information. Polychlorinated biphenyls (PCBs), organochlorine pesticides (such as DDT), metals (such as mercury and lead), and air pollutants (including polycyclic aromatic hydrocarbons and particulate matter) were the most frequently studied across the literature.

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Chemical exposures examined in DOHaD epidemiology studies (1988-2014)

Just because these chemicals are the most highly studied does not necessarily mean that they are the most harmful, however. This research could be subject to observational bias from the “streetlight effect,” and investigators may be overlooking other chemicals that also disrupt early life processes.

Concerning Outcomes

The vast majority of DOHaD work to date has examined neurobehavioral and neurodevelopmental outcomes, such as changes in IQ and executive function. The authors hypothesize that one of the reasons that these outcomes have received the most attention is that there are multiple relevant assessments that can be performed in early life. By contrast, outcomes with longer latency periods or fewer clear assessment methods may pose challenges for researchers.

Less frequently studied DOHaD outcomes included cancer as well as adverse impacts on the respiratory, reproductive, immune, and metabolic systems. [Note: companion publications in this journal issue provide reviews of the developmental origins of reproductive disorders and metabolic disorders.] Very few studies have focused on the cardiovascular system, thyroid regulation, and gastrointestinal system, among others.

Key Areas for Future Research

Additional Exposure Periods

Most DOHaD studies have focused on environmental exposures that occur in utero. Research on this vulnerable period is extremely important, yet exposures during other periods of life can be problematic as well.

For example, emerging evidence suggests that even preconception exposures in the mother and father – particularly to persistent pollutants or to chemicals and experiences that alter epigenetic marks– may impact child health outcomes.

Additionally, because of the substantial brain changes that take place between the last trimester of pregnancy and two years of age, the “first 1000 days of life” movement has highlighted the importance of optimal nutrition during the prenatal and postnatal period. If the young brain can be affected by nutrition, it can also be altered by environmental pollutants – and thus studies that capture this timeframe are crucial.

Additional Outcomes

As mentioned above, much of the research in the field of DOHaD has focused on the neurodevelopmental consequences of early life exposures. In the coming years, researchers should also expand their work to other organ systems and processes, such as the cardiovascular, immune and gastrointestinal systems.

Moreover, while challenging, researchers should attempt to address the possibility that exposures may impact multiple biological processes through related pathways. For example, given the central role of hormonal signaling in the body, it is highly plausible that disruption of these processes could lead to adverse effects on the reproductive system, neurological system, and metabolic system, among others.

Additional Chemical Exposures

Persistent pollutants and metals have dominated the DOHaD field, perhaps because exposure information is more easily obtainable. More recent efforts have utilized advanced methods to examine additional chemicals, and future research should continue to assess a broadened group of exposures. Even chemicals that are non-persistent (short-lived) in the body may be problematic, particularly if their ubiquitous presence in our society ensures near constant exposures.

In addition, given that 1) combinations of chemicals may act differently than single chemicals, and 2) we are all exposed to numerous chemicals at the same time, it will be important to examine the effects of early life exposures to complex mixtures.

Later Life Assessment of Adverse Health Outcomes

The authors note that of the 425 publications reviewed, only 43 examined adverse outcomes in individuals over the age of 18. Thus, the environmental health field lacks the long-term follow-up that would provide evidence comparable to Barker’s early work on adult cardiovascular outcomes.

Such studies are challenging and costly; yet, they are crucial for elucidating the implications of exposures over the life course. Continued funding of longitudinal cohorts over extended periods of time will ensure that these data are generated.

Systematic Review

The purpose of this work was not to draw conclusions about the strength of the evidence of links between certain chemicals and outcomes. The authors did, however, suggest that the most commonly studied chemical/outcome combinations may be ready for systematic reviews, including:

  • Pesticides and cancer
  • Air pollution and respiratory effects
  • Organochlorine pesticides and respiratory effects
  • Polyfluoroalkyl substances (PFAS) and immune outcomes

My Take on the Bottom Line: Science & Ethics

This summary of DOHaD literature from an environmental health perspective can direct researchers to focus their future work on key areas that need further attention, as noted above. Continued epidemiological research, in conjunction with toxicological studies that can elucidate mechanistic pathways, will help advance our understanding of the implications of early life exposures.

Yet for many chemicals, such as lead, there is already ample evidence of harm from early life exposures. In this situation – and as data continue to be generated for other chemicals in the coming years – the essential next step is to take action to protect children during vulnerable periods of development.

As described in “Science and Social Responsibility in Public health,” “…environmental health researchers have a joint responsibility to acquire scientific knowledge that matters to public health and to apply the knowledge gained in public health practice.”

This responsibility not only to conduct strong research but also to ensure implementation of science-based policies is our ethical duty – and the health of the next generation depends on it.

How the U.S. is taking the lead to prevent lead poisoning

This piece was first published on the Interdisciplinary Association for Population Health Science (IAPHS) blog. You can see the original posting here.  

The crisis in Flint, Michigan, returned our attention to a problem that we would have preferred to believe was behind us: lead poisoning. This incident highlighted the dangers of lead-lined water pipes; but, unfortunately, there are numerous other sources of lead exposure throughout the United States. I’ve written previously about risks from contact with contaminated soil or through the workplace. Lead-based paint, outdoor air, and manufactured products also pose risks. Because of these diverse sources, eliminating lead poisoning is challenging and requires coordination across multiple programs and policies.

Understanding this complex need—and perhaps sensing the increased public concern regarding lead in the United States—the President’s Task Force on Environmental Health Risks and Safety Risks to Children recently released a report entitled “Key Federal Programs to Reduce Childhood Lead Exposures and Eliminate Associated Health Impacts.” This report describes the dozens of federal regulations and programs that have been established to address lead exposures in children. It also marks progress towards the development of an enhanced lead strategy that will address existing policy gaps.

The report is worth a read; you may be surprised by the number of existing policies and efforts aimed at mitigating lead exposure. There are almost 60 programs and activities administered by nine agencies and close to 30 specific regulations that address lead exposures, directly or indirectly, in children. Some of these programs and regulations include:

Together, all of these efforts have contributed to the impressive decline in blood lead levels in this country, as illustrated in the figure below.


Despite this progress, significant challenges remain. Exposure to lead occurs disproportionately in minority and low-income families, and future work should focus on mitigating this disparity. As prescribed by Executive Order 12898, environmental justice must be a core component of agency activities.

To meet these environmental justice goals and continue to reduce lead exposure across the country, continued funding of these programs is essential. This report demonstrates that eliminating lead hazards requires parallel efforts and synergies between nine different government agencies—from the EPA to HUD, and the Department of Education to the Department of Transportation. Therefore, in the coming years, we must ensure that these agencies continue to receive the resources to be able to adequately address this critical public health issue. Call or write your representatives to voice your thoughts on the importance of protecting funding for public health agencies.

We have come so far in addressing lead in this country; let’s make sure we can finish the job completely.

A Decade into the “Vision,” Environmental Health gets a Progress Report

This year represents an important 10-year milestone for science and society.

No, I’m not referring to the 10th anniversary of the Apple iPhone, though that has undoubtedly changed all of our lives. Rather, 2017 marks ten years since the National Academy of Sciences (NAS) released its seminal report, Toxicity Testing in the 21st Century: A Vision and a Strategy.

In that report, the NAS laid out a vision for a new approach to toxicology that incorporates emerging cell-based testing techniques, rather than costly and time-intensive whole animal models, and utilizes early biological pathway perturbations as indications of adverse events, rather than relying on evaluations of end disease states. Tox21 and ToxCast, two federal programs focused on using alternative assays to predict adverse effects in humans, were initiated as first steps in this strategy. In the years since its release, the report has profoundly shaped the direction of environmental health sciences, particularly toxicology. (An analogous exposure sciences report, Exposure Science in the 21st Century: A Vision and a Strategy, was published in 2012.)

Now, one decade later, the NAS has reviewed progress on these efforts in its recently released report, Using 21st Century Science in Risk-Based Evaluations.

How are we doing, and what are next steps?

Overall, the committee supports efforts to use data from new tools, such as biological pathway evaluations, in risk assessment and decision-making. (Of course, limitations should be clearly communicated, and tools should be validated for their specific purposes.) Several case studies are described as examples of situations where emerging tools can be useful, such as quickly prioritizing chemicals of concern or evaluating risks from chemical mixtures at a contaminated site.

This report also documents advancements and challenges for each of the three interconnected fields of environmental health sciences: toxicology, exposure science, and epidemiology. I’ve summarized some of these key points in the chart below, and additional (digestible) information is available in the NAS report summary.



Recent Advancements

Key Challenges


  • Incorporate metabolic capacity in in vitro assays
  • Understand applicability & limitations of in vitro assays
  • Improve biological coverage
  • Address human variability & diversity in response

Exposure Science

  • Coordination of exposure science data (ex: databases)
  • Integration of exposure data of multiple chemicals obtained through varied methods


  • Improved data management & data sharing
  • Improved methods for estimation of exposures

I won’t go into detail on all of these points, but I do want to highlight some of the key challenges that the field of toxicology will need to continue to address in the coming years, such as:

  • Improving metabolic capacity of in vitro assays: Cell-based assays hold promise for predicting biological responses of whole animals, but it is critical to remember that these new tools rarely reflect human metabolic capacity. For example, if a chemical is activated or detoxified by an enzyme in our bodies, reductionist assays would not adequately reflect these changes – and thus their prediction would not be fully relevant to human health. We need continued work to incorporate metabolic capacity into such assays.
  • Improving biological coverage: An analogy that I’ve often heard in relation to the limitations of these new tools is that they are only “looking under the biological lamp post.” Essentially, we can only detect effects that the assays are designed to evaluate. So, we need further development of assays that capture the wide array of possible adverse outcomes. And we cannot assume that there is no hazard for endpoints that have not been evaluated.

New models of disease causation

Not only is the environmental health science ‘toolkit’ changing but also our understanding of disease causation. As discussed in the report, 21st century risk assessment must acknowledge that disease is “multifactorial” (multiple different exposures can contribute to a single disease) and “nonspecific” (a single exposure can lead to multiple different adverse outcomes). This advanced understanding of causality will pose challenges for interpreting data and making decisions about risk, and we will need to incorporate new practices and methods to address these complexities.

For example, we can no longer just investigate whether a certain exposure triggering a certain pathway causes disease in isolation, but also whether it may increase risk of disease when combined with other potential exposures. It gets even more complicated when we consider the fact that individuals may respond to the same exposures in different ways, based on their genetics or pre-existing medical conditions.

The Academy suggests borrowing a tool from epidemiology to aid in these efforts. The sufficient-component-cause model provides a framework for thinking about a collection of events or exposures that, together, could lead to an outcome.


Sufficient-component-cause model. Three disease mechanisms (I, II, III), each with different component causes. Image from NAS Report, Using 21st Century Science to Improve Risk Related Evaluations


Briefly, each disease has multiple component causes that fit together to complete the causal pie. These components may be necessary (present in every disease pie) or sufficient (able to cause disease alone), and different combinations of component causes can produce the same disease. Using this model may promote a transition away from a focus on finding a single pathway of disease to a broadened evaluation of causation that better incorporates the complexities of reality. (I’ve blogged previously about the pitfalls of a tunnel-vision, single pathway approach in relation to cancer causation.)

Integration of information, and the importance of interdisciplinary training

As the fields of toxicology, exposure science, and epidemiology continue to contribute data towards this updated causal framework, a related challenge will be the integration of these diverse data streams for risk assessment and decision-making. How should we weigh different types of data in drawing conclusions about causation and risk? For example, what if the in vitro toxicology studies provide results that are different than the epidemiology studies?

The committee notes that we will need to rely on “expert judgment” in this process, at least in the short term until standardized methods are developed. And they discuss the need for more interaction between individuals from different disciplines, so that knowledge can be shared and applied towards making these difficult decisions.

One issue that was not discussed, however, is the importance of training the next generation of scientists to address these complex challenges. Given the inevitable need to integrate multiple sources of data, I believe it is critical that the students in these fields (like me!) receive crosscutting training as well as early practice with examples of these multi-faceted assessments. Some programs offer more opportunities in this area than others, but this should be a priority for all departments in the coming years. Otherwise, how can we be prepared to step up to the challenges of 21st century environmental health sciences?

Looking forward

Speaking of challenges, we certainly have our next decade of work cut out for us. It is amazing to think about how much progress we have made over the last ten years to develop new technologies, particularly in toxicology and exposure sciences. Now we must: refine and enhance these methods so they provide more accurate information about hazard and exposure; address the complexities of multifactorial disease causation and inter-individual susceptibility; and work across disciplines to make decisions that are better protective of public health and the environment.

Election Reflections: Women in Science

It goes without saying that the outcome of the recent U.S. presidential election was a shock. I will avoid a long-winded discussion of the associated consequences and just acknowledge that we came painfully close to electing the first female president of the country.

In the weeks leading up to the election, I had felt a contagious energy among my female friends – a great hope that we could have a role model in the highest office of the country.

I don’t have presidential aspirations, however. So, upon further reflection, I realized that much more important to my own growth and ambitions has been the presence of female role models in my field of environmental health sciences. Unlike for my mother, who had few women role models in her early days in public health, I feel fortunate to have numerous, highly successful female scientists to look up to. Because of these inspiring women (including my mother!), I have never doubted the possibility that I can achieve my professional goals.

Perhaps my earliest model of a female scientist and change-maker was Rachel Carson, whose pioneering environmental work I learned about during elementary school. While I probably did not understand the full scope of her impact at that young age, I was evidently motivated enough by her story to dress up as Carson during career day.

Years later, during college, I read Our Stolen Future, an eye-opening book that Al Gore has referred to as a sequel to Carson’s Silent Spring. Who better to learn from about endocrine disruption than the late Theo Colborn, co-author of this book and a visionary leader who is often called the “mother of endocrine disruption?” Reading this work provided immediate clarity and direction to my undergraduate studies. After college, as I began to further immerse myself in the world of environmental health at Environmental Defense Fund, I became increasingly inspired by the work of Colborn and the many other contemporary female scientists who are shaping the field.

Women are leading some of today’s most important science policy and advocacy efforts, and I have had the privilege to interact with several of these amazing individuals. I greatly admire Sarah Vogel (Environmental Defense Fund) Ruthann Rudel (Silent Spring Institute), Jennifer Sass (Natural Resources Defense Council), and Molly Rauch (Moms Clean Air Force), among others, for their efforts to promote the translation of strong science into health protective policies.

All science is a team effort, of course, but female scientists across the country have led many of the studies that these and other organizations draw upon in their public health work.

  • Ruthann and her team at Silent Spring Institute have conducted important and innovative work related to endocrine-active chemicals and breast cancer risk.
  • North Carolina has the preeminent Heather Duo: Heather Stapleton at Duke University, who researches routes of exposure to flame retardants, and Heather Patisaul, at North Carolina State University, who is examining the effects of chemical exposures on the neuroendocrine (brain & hormonal) system.
  • Dana Dolinoy, at the University of Michigan, is a leading expert in epigenetics (changes in how a gene is expressed rather than a change in the genetic code itself).
  • Tracey Woodruff and her team at the UCSF Program on Reproductive Health and the Environment have done extensive work in diverse areas, ranging from advancing methods for systematic review to assessing prenatal chemical exposures.
  • Frederica Perera, at Columbia University, pioneered the field of molecular epidemiology (using specific biomarkers to understand the link between environmental exposures and disease).
  • Irva Hertz-Picciotto, at the University of California, Davis is a top environmental epidemiologist with a particular focus on the environmental factors that contribute to autism. (She recently co-founded Project TEDNR, a collaborative initiative involving scientists, policy-makers, and advocates that aims to reduce exposures to neurotoxicants.)

I could go on and on (and on), but you get the idea. Women are making waves in environmental health sciences through their robust, cutting-edge research.

Government is no exception. I am excited by the work of early career scientists, such as Tamara Tal, who is conducting innovative toxicological studies in zebrafish at the Environmental Protection Agency (EPA), and Kelly Ferguson, an environmental epidemiologist at the National Institute of Environmental Health Sciences (NIEHS) who studies how chemical exposures during pregnancy impact child health and development. And, I am inspired by the many women who are leaders within these agencies, such as Elaine Cohen-Hubal (Integrated Systems Toxicology Division, EPA), Kristina Thayer (Office of Health Assessment and Translation, NIEHS) Dale Sandler (Chronic Disease Epidemiology, NIEHS), and Nicole Kleinstreuer (National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods, NIEHS).

We also have two phenomenal and highly accomplished women leading our environmental and public health agencies: Gina McCarthy (EPA) and Linda Birnbaum (NIEHS).

These are all women who I look up to tremendously and whose work I follow closely. But, on a more personal level, I have been fortunate to work directly with several amazing female scientists during my training so far. Pamela Lein (University of California, Davis) Stephanie Padilla (EPA), Elaine Faustman (University of Washington, Seattle), Sheela Sathyanarayana (University of Washington, Seattle), and Lianne Sheppard (University of Washington, Seattle) have all provided valuable mentorship and guidance to me.

So, while we do not yet have our first female president, this post is my way of acknowledging all of the incredible female scientists who have impacted my life through their work in environmental health sciences. Because of these inspiring, accomplished women (and the numerous others who I have not mentioned for the sake of brevity), I do not feel limited when I imagine my future. I have confidence that, with hard work and dedication, I can achieve what I set my mind to.

Thank you for being role models to me and the many other aspiring environmental health scientists of my generation!

Me, in elementary school, already aspiring to follow in Rachel Carson’s footsteps

Lead exposure beyond Flint—protecting our nation’s workers

This commentary was published in the September 12, 2016 edition of Environmental Health News‘ Above the Fold. To view the original version, click here: http://www.environmentalhealthnews.org/ehs/news/2016/sept/commentary-lead-exposure-beyond-flint2014protecting-our-nation2019s-workers 

By Rachel Shaffer and Steven Gilbert
Environmental Health News

Lead poisoning returned to the national consciousness this year through the tragic events in Flint, Michigan, but drinking water is only one of many exposure routes. Because of outdated federal workplace safety standards, acute and chronic occupational lead exposure occurs all too often and can harm workers and their children, who may be exposed prenatally or through lead dust carried into the home. We need to protect workers and their families by updating federal workplace lead standards based on the latest scientific research.

The U.S. Occupational Safety and Health Administration (OSHA) regulates workplace lead exposure at the national level through two standards, the general industry standard and the construction industry standard. Both of these standards are severely outdated, based on information available in the 1970s instead of the latest scientific and medical evidence.

Image adapted from CDC/NIOSH

Thus, while OSHA’s mandate is to “assure so far as possible every working man and women in the Nation safe and healthful working conditions,” these goals have not been met for workplace lead exposure.

Under the existing regulations, workers can be exposed to levels of lead that result in 60 micrograms of lead per deciliter of blood before medical removal is required, and they can return to work after their blood lead levels are as high as 40 micrograms per deciliter.

As comparison, the Centers for Disease Control (CDC) defines blood lead levels above 5 micrograms per deciliter as “elevated” and has set a “Healthy People 2020” national public health goal that aims to reduce the proportion of workers with blood lead levels above 10 micrograms per deciliter.

Exposure to levels of lead much lower than what is allowable under OSHA’s current standards have been linked to high blood pressure, decreased kidney function, reproductive effects and neurological impairments.

In industries with high potential for lead exposure, such as construction, gun ranges, and battery reclaiming/manufacturing, not only are workers at risk, but their families may also be exposed inadvertently through take-home lead dust.

Children’s developing nervous systems are particularly vulnerable, and lead exposure can result in intellectual impairment. Stricter standards that require lower workplace lead levels and better personal protection will substantially reduce the dangers associated with take-home lead exposures.

In addition, since lead released from bones during pregnancy easily crosses the placenta, children born to lead-exposed workers are at risk for neurodevelopmental and other adverse health effects. Better standards will reduce potential fetal lead exposure in female workers of childbearing age.

Both California and Washington State are in the process of updating their own occupational lead standards. But, why should workers in only two states be privileged to improved health protections? OSHA standards, which cover all workers across the country, should also be strengthened to adequately protect workers and their families.

In the interim, though, enforcement of company compliance with existing federal regulations is also critical. A recent blog post from the U.S. Department of Labor described a case in which OSHA officials responded to worker complaints and cited a Wisconsin shipyard operator with 19 willful violations of the lead standard after detecting elevated blood lead levels in 75 percent of employees tested.

OSHA regulates workplace lead exposure at the national level through two standards. Both of these standards are severely outdated.The incident illustrates the importance of maintaining a well-funded OSHA ensuring it has the resources to monitor adherence to the standards. However, a draft bill for fiscal year 2017 suggests that OSHA’s budget would be cut significantly, which may prevent these enforcement activities and thus put workers at further risk.

We have the scientific and medical evidence that documents the harms of elevated blood lead levels, and we have the technology to reduce occupational lead exposure.

Now it is time to take action to put elevated workplace lead exposure behind us by rapidly adopting a standard that is aligned with CDC’s existing public health guidance, which classifies blood lead levels above 5 micrograms per deciliter as elevated.

We must strengthen OSHA standards for lead and provide sufficient support for the agency’s enforcement actions. The health of our workers – and their children – depends on it.

Ancient philosophy, modern toxicology

The whole is greater than the sum of its parts.”
– Aristotle (384 BC-322 BC)


Aristotle was talking about metaphysics and the emergent theory, but his insight corresponds to an important emerging theory in environmental health: combinations of different chemicals acting together in our bodies can produce larger (or different) effects than would be seen if each chemical were acting independently. In technical terms, this is called “synergism.”

Why does this matter? Through the course of our daily lives, we are all exposed to hundreds of different types of chemicals. Most laboratory toxicity studies, however, only assess the effects of a single compound in a carefully controlled environment. Consequently, the (very limited) data that we have on chemical hazard do not actually reflect real-world exposure situations (ie: co-exposures to mixtures of chemicals). Researchers are beginning to address this deficiency, though, and initial results suggest that Aristotle’s ancient wisdom is eerily relevant to modern-day toxicology.

A recent study published in the journal Toxicological Sciences examined the interaction between polycyclic aromatic hydrocarbons (PAHs) and arsenic. PAHs are organic pollutants that are produced during combustion processes (including from tobacco). Many PAHs, such as benzo[a]pyrene, can cause DNA damage and are known or suspected to cause cancer. Arsenic is a naturally occurring element that can exist in different chemical forms. The inorganic form As+3 can interfere with DNA repair and is linked to skin diseases and cancer. Human exposure to As+3 often occurs through ingestion of contaminated drinking water or rice-based products. Many people around the world are exposed to both PAHs and inorganic arsenic simultaneously, but little is known about how these two chemicals — one that causes DNA damage, and one that interferes with DNA repair – act together in the body.

For this work, researchers examined the effects of As+3 and three specific PAHs (benzo[a]pyrene and two metabolites, BP-Diol and BPDE) separately and together in mouse thymus cells (precursors to T-cells). Because T-cells serve a critical function in the immune system, chemical damage could lead to immune dysfunction.

After chemical treatment, the researchers measured the amount of DNA damage and DNA repair inhibition. At specific combinations of doses (one with As+3 and BP-Diol, and one with As+3 and BPDE), they saw a larger effect from treatment with two chemicals simultaneously than what would have been predicted from treatment with the same chemicals individually.

Next, they measured cell death (specifically, apoptosis) and found that while individual exposures to As+3 and BP-Diol did not increase death, exposure to the compounds together caused a synergistic increase in the percentage of dead cells. One possible explanation for this result is that at low levels of separate exposure, the body can adapt to prevent damage. But perhaps with the two chemicals together, the system is overwhelmed and cannot compensate.

Overall, based on these and other related results in this study, the researchers hypothesized that the As+3 increases the toxicity of certain PAHs through its ability to inhibit DNA repair pathways. As I noted above, PAHs alone can cause DNA damage. With the addition of As+3, which interferes with DNA repair during normal cell cycle replication, cell damage is even greater.

Previous work had documented the existence of similar interactions between PAHs and arsenic, but those studies had used high doses that were not representative of potential human exposures. This study, by contrast, investigated the effects of low-level exposures that are more similar to what we might encounter in the environment.

One important caveat of this work is that the researchers conducted the experiment in isolated mouse thymus cells. In vitro systems (or “test tube experiments”) are increasingly common in toxicology, as the field aims to find alternatives to whole animal testing. However, there are obvious limitations to these models. Not only are mouse cells different from human cells, but these mouse thymus cells are separated from the rest of their system and may not represent how a fully functional organism responds and/or adapts to a toxicant exposure. As follow-up, researchers should test this chemical combination in a relevant animal model to see whether similar results are obtained.

Nevertheless, this study provides important evidence of synergistic effects from low-level exposures to two common environmental contaminants. And these data may be just the tip of the iceberg. What other potential interactions exists between the thousands of other chemicals that we are exposed to over the course of our lives? The challenge with synergistic interactions is that they cannot always be predicted from testing individual chemicals. (I’ve written about this previously, specifically with regard to cancer processes.) It is daunting to think about testing all of the potential combinations that may exist, since our public health agencies are struggling to generate even basic toxicity data on all of these chemicals individually.

I wish we could consult Aristotle on this problem.

One strategy to start to address this challenge could be to prioritize testing combinations of chemicals that – like the pair chosen in the study described here – are most common across the population. Existing biomonitoring efforts, such as the U.S. National Health and Nutrition Examination Study (NHANES), could guide the selection of appropriate mixtures. Testing these highly relevant chemical combinations could provide valuable information that could be immediately translated into risk calculations or regulatory standards.

As Plato, another great ancient thinker said, “the beginning is the most important part of the work.” So, while it is definitely overwhelming to think about tackling the question of chemical combinations, it is crucial that we take first steps to make a start.

Outdated lead standards put Washington workers, families at risk

This op-ed originally appeared in the August 1, 2016 print edition of the Seattle Times. See here for the online posting: http://www.seattletimes.com/opinion/outdated-lead-standards-put-washington-workers-families-at-risk/ 


FGGM_Pb5Image credit:  https://phc.amedd.army.mil/topics/phcrspecific/north/Pages/IHD.aspx

By Rachel Shaffer and Steven Gilbert

THE tragedy in Flint, Mich., thrust lead contamination into the spotlight, and much attention has been focused rightly on the terrible consequences of childhood lead exposure.

Most people, however, are unaware that adults can also experience serious health effects from lead. As with many chemicals and hazards, workers are often more highly exposed than the general population. Examples of industries with high potential for lead exposure include construction and battery manufacturing. In these and other industries, not only are workers at elevated risk, but their families may also be exposed inadvertently through take-home lead dust.

In Washington state, there are two primary standards that regulate occupational exposure to lead: the “general industry lead standard” and the “lead in construction standard.” Unfortunately, both of these standards are severely outdated, based on information available in the 1970s instead of the latest scientific and medical evidence.

Under the existing inadequate standards, workers can be exposed to levels of lead that result in blood-lead levels up to six times higher than the Centers for Disease Control and Prevention’s maximum health goal for adults.

Moreover, levels of lead much lower than Washington state’s current standard have been linked to high blood pressure, decreased kidney function, reproductive effects and neurological impairments. Standards should change to reflect the latest public-health recommendations and scientific evidence.

To adequately protect workers and their families, blood-lead levels must be routinely monitored when there is any possibility of lead exposure, and individuals should be removed from their duties when their blood-lead levels are above the National Institute of Occupational Safety and Health’s reference level for adults.

We have the technology to drastically reduce occupational lead exposure. We need to give workers the safe workplaces they deserve.

The health benefits of updated occupational lead standards would extend beyond workers and would also protect their children and families.

Workers often inadvertently carry lead dust on their skin and clothing when they return home, which can cause lead poisoning among family members. Stricter standards that require lower workplace lead levels and better personal protection would substantially reduce take-home lead exposures.

Second, since lead easily crosses the placenta during pregnancy, children born to lead-exposed workers are at risk for neurodevelopmental and other adverse health effects. Better standards would reduce potential fetal lead exposure in female workers of childbearing age.

The state Department of Labor and Industries should move swiftly to update our existing outdated lead standards. Workers in this state should not be subject to the health risks of lead exposure. Nor should their children suffer the secondhand consequences of this well-known poison.

It’s time to take action and give our workers and their families the protection they deserve.

For additional information on the Washington State process to update the occupational lead standard, please visit: http://lni.wa.gov/Safety/Rules/WhatsNew/LeadSafety/default.asp


Reflections on Reform

There has been no shortage of news articles and blog posts about the recent passage of the Frank R. Lautenberg Chemical Safety for the 21st Century Act, which amends the ineffective and outdated 1976 Toxic Substances Control Act (TSCA). And, you probably don’t need to read another description of the strengths and weaknesses of the ultimate compromise. (If you do want a quick primer on why this reform matters, though, I would recommend this NPR interview with my former boss, Richard Denison, or his post on why this is a “really big deal.“)

Nevertheless, I want to add some reflections of my own on this historic occasion.

As a student in the environmental health field, this bill is particularly significant to me. Not only does the reform directly influence issues that I think about constantly, both personally and academically, but it will also likely set the stage for my future career.

It is exciting to think that I, along with fellow classmates in toxicology, environmental epidemiology, and exposure science programs across the country, will soon be able to participate directly in the implementation of this updated chemical safety system. We can feel a new sense of possibility with our work, instead of the backdrop of futility that comes when we learn in our foundational courses that – despite the damning evidence- the Environmental Protection Agency (EPA) could not even ban asbestos(!). With that (previous) reality in mind, could there be any hope that our efforts studying other potentially harmful chemicals would ever make an impact? As an analogy, what if there were a law that prevented the Centers for Disease Control and Prevention (CDC) from implementing effective vaccination programs? How would budding infectious disease epidemiologists feel about their opportunities for contributing to real public health advancements? Now, with the Lautenberg Act, we have a new framework in place that will at least offer the chance for us to use our research to make a difference. I hope that this will inspire others to join this dynamic, interdisciplinary field.

TSCA reform will impact and energize many aspects of environmental health. For example, the new mandate for safety reviews of all chemicals in active commerce will require investment in efficient and accurate screening tools. New testing technologies are already being developed, but further work and innovation – as well as input from a diverse array of scientists – will be necessary to ensure their reliability, relevance, and validity.

In addition, this reform will likely spur more research to understand the unique susceptibility of certain populations. The bill contains provisions that explicitly require protection of “potentially exposed or susceptible population[s].” This category includes “infants, children, pregnant women, workers, and the elderly,” but also other individuals who may be “susceptible to greater adverse health consequences from chemical exposures than the general population” – for example, because of their genetics. The study of gene-environment interactions (also known as “toxicogenetics”) aims to investigate specific genes that make some individuals more sensitive to chemicals. Dr. Francis Collins, director of the National Institutes of Health, summed up this idea with the phrase “genetics loads the gun, but the environment pulls the trigger.” Toxicogenetics is already a rapidly growing field, but I anticipate future work in this area will be crucial in helping us to determine the levels at which regulations should be set to ensure protection for those who are most vulnerable.

While there will likely be numerous positive consequences of the reform bill, the success of this updated chemical policy system is far from guaranteed. Numerous roadblocks may appear, such as the possibility of a mismanaged EPA or the paralyzing impact of endless cost-benefit analyses in risk management decisions. Passing TSCA reform was a difficult and momentous task, but the hard work will continue. We must maintain pressure to hold EPA accountable, prevent entanglement by special interests, and ensure the law is executed correctly. And, Congress must provide adequate funding to environmental health research programs, which will produce key scientific evidence to guide EPA and educate the next generation of scientists (like me!).

This compromise was not perfect, but the bill does represent a real improvement over the status quo. Now, the environmental health community has an exciting chance to help make its enactment as strong as it can be, through robust research and continued advocacy.

I can’t wait to play my part.


Watch Your Step: Lead Lurking in the Soil

Thursdays are one of my favorite days of the week. Not because the weekend is approaching, but because it is when the UW Department of Environmental and Occupational Health Science seminar series takes place. Each week, an outside speaker joins us to discuss his/her research. I often leave inspired, with broadened interests, and a renewed excitement and passion for the environmental health field.

This week was no exception. I had the privilege of hearing Dr. Howard Mielke discuss his area of expertise: lead contamination in cities.

Lead has been front and center in the news recently. From the tragedy in Flint to emerging concerns about lead contamination in schools around the country, we are all now highly aware of the fact that our water supply may not be appropriately protected from outdated and dangerous lead pipes.

However, Mielke’s presentation did not focus on lead pipes. Nor the other common exposure source that I was familiar with, lead paint. Instead, he emphasized lead in soil.

Digging into the facts about lead in soil

How did lead end up in the soil?

Leaded gasoline.

Before leaded gasoline was phased out in the US in 1996, lead was emitted from tailpipes as a volatile compound (PbBr2) but quickly reacted to form a non-volatile compound (PbSO4) that precipitated to the ground (for more on the atmospheric chemistry of lead, see here and here). Thus, for years, we had millions of cars spewing lead not only into the air but also onto the ground all around us.

These automobile-related lead emissions resulted in several trends, including:

Such widespread lead contamination in the soils around our homes was a surprise to me, and these distinct patterns emphasize the terrible, lingering legacy of leaded gasoline.

But, could this really be an important exposure source, given all of the attention on lead paint and pipes?

Part of answering this question involves understanding that child blood lead levels exhibit a well-documented seasonal pattern: higher levels in the summer, and lower levels in the winter.

[from Laidlaw et al, 2016: Children’s Blood Lead Seasonality in Flint, Michigan (USA) and Soil-Sourced Lead Hazard Risks]

What could account for this variation? Mielke and others suggest that in the summer months, children spend more time outside, playing in the yard. Lead-contaminated soil ends up on their hands, on their faces, and, likely also, in their mouths. In addition, soil dust tends to be drier in the late summer and can be easily inhaled. The observed seasonal patterns suggest that lead in soil accounts for a large part of child lead exposure. If lead paint were the main source of exposure, then we would probably see peaks in the winter, when kids are cooped up inside.

A solution for soiled soil?

While replacing leaded pipes seems like a tall task, eliminating lead in the soils around us feels even more overwhelming. Mielke has led efforts in the New Orleans area to bring in clean dirt to layer on top of lead-laden dirt (for example, in children’s playgrounds). But widespread implementation of massive soil-shifting projects seems unlikely.

Perhaps a better solution is to invest in emerging bioremediation techniques, using plants and microbes?

Big picture, though, Mielke advocates for a “Clean Soil Act,” analogous to our Clean Water Act or Clean Air Act, to provide the appropriate protections for the earth beneath our feet. (In fact, he helped develop a Clean Soil Act for Norway).

In the meantime, parents should be aware of this often overlooked source of child lead exposure. In addition, it is important for urban gardeners take appropriate precautions, since lead and other heavy metals can be absorbed in plants – thereby posing potential risks through dietary intake. (For more on heavy metals in gardens, check out Environmental Health Perspectives’ Urban Gardening: Managing the Risks of Contaminated Soil)

A lesson from the past?

In closing, I’ll share one of my favorite slides from Mielke’s presentation (see image below).


He displays a quotation from Yandell Henderson, a Yale professor who vehemently protested against adding lead to gasoline during a hearing in 1925. He warned that society was at a crossroads, facing “the question whether…the action of the Government is guided by [scientific] advice; or whether commercial interests are allowed to subordinate every other consideration to that of profit.”

Unfortunately, we know how that particular story ended up.

And while there have been numerous similarly discouraging stories in the realm of chemicals and children’s health, I’m still hopeful that one day soon, our country will be ready to take the other road – prioritizing public health and environmental protections over profits.