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 Because of outdated federal workplace safety standards, acute and chronic occupational lead exposure occurs all too often and can harm workers and their children, who may be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 Both of these standards are severely outdated, based on information available in the 1970s instead of the latest scientific and medical evidence.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.

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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.

ijerph-13-00358-g001-1024
[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).

IMG_3763

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.

Domestic legislation with international implications?

Take a look at these three world maps. Does anything stand out to you?

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For interactive versions of these maps, visit the Synergies Among the Basel, Rotterdam, and Stockholm Conventions webpage (also the source for these static images)

 

Maybe the uninspiring shade of grey that covers the United States in each one?

Yes, that’s what caught my attention as well.

These maps indicate member countries for the Stockholm Convention, the Rotterdam Convention, and the Basel Convention, respectively. The Stockholm Convention aims to eliminate or restrict Persistent Organic Pollutants, or “POPs,” which are toxic chemicals that persist in the environment and build up in organisms. The Rotterdam Convention promotes open exchange of information about specific pesticides and industrial chemicals. And, the Basel Convention focuses on the management of hazardous waste. Member countries (indicated by color coding on each of the maps above) can participate and negotiate in the relevant discussions. The United States, along with countries such as South Sudan, Myanmar, Iraq, and Uzbekistan, has not officially ratified the treaties.

The obstacle to forward movement on this issue is Congress (surprise, surprise). As with any international treaty, approval requires the “advice and consent” of two thirds of the Senate. But before this vote can take place, Congress needs to amend existing federal laws – the Toxic Substances Control Act (TSCA), the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), and the Resource Conversation and Recovery Act (RCRA) – so the U.S. is able to comply with the treaties (for example, to give EPA the authority to regulate chemicals listed). Over the years, several relevant amendments have been proposed, but none have passed..

The chemicals regulated in these treaties are among the worst of the worst – dioxins, PCBs, DDT, as well as several multi-syllabic pesticides – and they tend to migrate long distances through wind, water, and biological organisms. EPA needs to have the ability to take appropriate actions on these chemicals, and others added in the future, to protect public health and the environment.

By abstaining from the treaties, the U.S. cannot negotiate for the addition of other dangerous compounds that may pose serious health risks to our population. (These chemicals do not respect borders, and pollutants released across the world can travel and cause harm here. The Alaskan Artic region is especially vulnerable). And, although U.S. taxpayers contribute to the Global Environment Facility – a fund that provides grants to assist countries on specific environmental improvement projects, including many related to the clean-up of POPs – we have no input on the use of these funds, since we are not members of the convention.

TSCA reform is currently under negotiation in the Senate and House, and while there have been intense discussions about many key components of the bill (such as state-preemption), minimal information is available regarding potential implications for these international treaties. However, it is crucial that the final legislation include such provisions, thereby paving the way for the U.S. to participate meaningfully in discussions regarding global chemicals of concern.

Environmental exposures and autism: decoding brain transcriptional patterns

Recent evidence indicates that individuals with autism exhibit characteristic gene expression changes in the brain. Specifically, they often have increased expression of genes related to immune and microglial function and decreased expression of genes related to synaptic transmission. Recognizing such patterns, researchers at the University of North Carolina-Chapel Hill asked an intriguing question: can these distinctive changes be used to identify chemicals that might contribute to risk of Autism Spectrum Disorder (ASD)?

For this work (recently published in Nature Communications), the researchers screened 294 chemicals from the US EPA ToxCast Phase I library in mouse cortical neuron-enriched cultures. While such 2D cultures do not represent the complexity of a fully functioning brain, it should be noted that gene expression profiles of their cultures revealed that their system was highly reflective of a whole embryonic brain during mid to late gestation (a critical period of development – the disruption of which has been linked to ASD).

After treatment, they monitored gene expression and created six clusters of chemicals based on the patterns of changes observed. While all of the chemical clusters represent potentially consequential biological changes, the researchers focused in particular on cluster 2, which up-regulated expression of immune and cytoskeletal-related genes and down-regulated expression of ion channel and synaptic genes. These patterns mirror changes observed in post-mortem ASD brains. (Interestingly, the gene expression changes also correlated with patterns observed in Alzheimer’s disease and Huntington’s disease, which suggests that neurodevelopmental and neurodegenerative diseases may share common pathways and pathology.) In addition to the observed gene expression changes, the cluster 2 chemicals also led to oxidative stress and microtubule disruption – effects that are implicated in neurodevelopmental and neurodegenerative disorders.

The results of this work are as unsettling as they are groundbreaking. The chemicals in cluster 2 are EPA-approved pesticides and fungicides: famoxadone, fenamidone, fenpyroximate, fluoxastrobin, pyraclostrobin, pyridaben, rotenone, and trifloxystrobin. (Rotenone might sound familiar to you; it has already been linked to Parkinson’s disease.) Several of these chemicals can be found at high concentrations on conventionally grown food crops, such as leafy green vegetables – yet another reason to buy organic. And, given that usage of some of these chemicals seems to be increasing (see Figure 7 of their paper), exposure across the population is a concern.

Correlation does not mean causation, however, and therefore this study does not prove that these chemicals trigger autism. Furthermore, as noted above, this study was conducted in cell culture using mouse neurons and therefore is not fully representative of what would happen in an actual human brain. But, we can use these findings as an important warning and should now prioritize these chemicals for further evaluation in animal studies (and also, perhaps, develop relevant epidemiological studies to monitor population-level effects given existing exposures).

While we lack general hazard information on most of the thousands of chemicals in commerce, the absence of information about potential developmental neurotoxicity is a particular problem. This study demonstrates that evaluation of gene expression changes could provide a screening-level assessment that might help to fill some of these concerning gaps. In addition, the authors suggest that their approach could be used to help identify therapeutics that could counter these disease-related gene expression changes – perhaps the first step towards treatment for this increasingly common condition.

Assessing new methods for detecting obesogens

The Environmental Protection Agency (EPA) has invested tremendously in its new toxicity-testing program, ToxCast, which aims to use in vitro high-throughput screening (HTS) assays to evaluate the effects of thousands of chemicals and prioritize them for further in vivo testing. Yet, many questions remain regarding the reliability and relevance of these assays. For example, are they providing accurate predictions about the effects of interest? Are the assays consistent over time and between laboratories? And, ultimately, do we have enough confidence in the results to use them as the basis for decision-making?

While EPA has begun to evaluate some of their assays, a recently published article in Environmental Health Perspectives reports specifically on the performance of ToxCast assays and related tools in detecting chemicals that promote adipogenesis. Such “obesogenic” chemicals interact with pathways involving the peroxisome proliferator activated receptor (PPARγ), among others, to alter normal lipid metabolism and contribute to abnormal weight gain. (Note: the term “obesogen” was coined by Bruce Blumberg, the senior author of this paper).

For the first part of this work, the researchers evaluated ToxCast results for one specific pathway in adipogenesis. Of the top 21 chemicals that were reported to bind to PPARγ in ToxCast Phase I, only 5 were actually found to activate PPARγ in their own laboratory.

Next, they examined the predictive power of multiple ToxCast assays representing various pathways related to adipogenesis. The researchers chose eight biologically relevant targets (including PPARγ) and generated a ToxPi (Toxicological Priority Index) graphic based on assay results for the chemicals (see figure from the paper, below). Each color represents a specific target evaluated by one or more assays, and larger slices correspond to higher relative activity in those assays. In this way, they could combine the results of multiple assays for each chemical and easily compare adipogenic potential.

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Adipogenesis ToxPis. Supplemental Figure from: Janesick et al, 2016: On the Utility of ToxCast and ToxPi as Methods for Identifying New Obesogens. Environmental Health Perspectives.

How well do these ToxPis – created based on weighted results from ToxCast assays – predict actual PPARγ activation and overall adipogenic activity? The researchers found that only 2 out of 11 highest scoring ToxPi chemicals could activate PPARγ in their laboratory assays, and only 7 out of 17 top and medium scoring ToxPi chemicals were active in cell culture adipogenesis assays. In addition, 2 of the 7 chemicals that appeared negative in ToxPi actually promoted adipogenesis in culture.

EPA had previously recognized the potential for false positive and false negatives in the testing program and had begun to implement correction methods, such as z-score adjustments, in more recent ToxCast phases. Unfortunately, problems remained even after researchers considered these supposed improvements. While many false positives and false negatives were removed, the true positives were also eliminated.

These results are concerning, to say the least. Why are the ToxCast assays performing so poorly in predicting PPARγ activity and overall obesogenic potential? The researchers suggest several possible reasons, including 1) the fact that there are relatively few specific obesogenic assays that have been developed (especially compared to estrogen and androgen receptor assays), and 2) the inherent difficulties in using simple receptor binding tests to reflect the complexities of the endocrine system.

These issues must be resolved if we are to move forward with the goal of using these assays for prioritization and risk assessment. Last year, EPA announced (see here and here) that they would allow the use of a combination of ToxCast estrogen receptor assays to replace several existing tests in the Endocrine Disruptor Screening Program (EDSP). Clearly, however, other areas of the ToxCast program need additional refinement and validation before they can be used confidently for regulatory purposes.

While it is discouraging to read about these weaknesses in ToxCast, such external assessments are essential and will motivate important improvements. With more input from and collaboration with the scientific community, we can be hopeful that EPA’s ToxCast program will be able to fulfill its goal of efficiently evaluating thousands of chemicals and serving as the basis for decision making to protect public health.

A sensitive test for skin sensitization

As the European Union moves away from animal testing for cosmetics, validation of alternative methods to assess the safety and hazards of compounds in such products is vital. Individual in vitro tests can provide key information on specific parts of the mechanism of disease, yet they may not be able to represent the multiple, sequential steps (what toxicologists refer to as the “adverse outcome pathway”) that result in the ultimate disease endpoint. An additional useful tool for chemical hazard identification is in silico modeling, which uses data on the structure or properties of compounds to predict their interactions with biological systems. There are many challenges with this approach, though, and previous in silico models have demonstrated limited accuracy.

However, researchers at George Washington University have developed a new modeling platform specifically for skin sensitization, CADRE-SS, that seeks to use different information in the prediction process. By incorporating data on molecular properties, rather than only on structure, to model the behavior of compounds in a biological environment, they have made significant improvements in the predictive capacity of such in silico tools.

To develop CADRE-SS, the researchers examined each part of the skin sensitization adverse outcome pathway — skin penetration, enzymatic activation, and protein binding — and then determined the specific physical-chemical properties or energy states that would lead to progression along the pathway. Linking these key chemical parameters for each part of the pathway allowed them to develop the final CADRE-SS model representing the whole skin sensitization process.

Initial tests demonstrated that this new model is highly accurate. Furthermore, not only is the model able to predict chemicals likely to cause skin sensitization, but it is also able to categorize chemicals based on their degree of sensitization potential (extreme, moderate, or weak) according on international classification systems.

If we ever hope to obtain health and safety information on the growing number of chemicals in commerce, then we must utilize methods other than traditional rodent testing (which is costly and time-intensive). Key data will likely come from a combination of in vitro, in silico, and high-throughput alternative animal assays. Thus, by improving the methods by which chemical activity in biological systems can be predicted, these researchers have moved us one step closer towards closing the existing data gap. In the future, these tools could also be used early in the chemical design process to screen out potentially problematic chemicals at the outset and direct companies towards the development of safer products.

Cancer Risk Assessment: Are We Missing the Forest for the Trees?

In recent years, national and international environmental public health organizations (including the US Environmental Protection Agency and the World Health Organization) have begun to use the adverse outcome pathway (AOP) and/or mode of action (MOA) as unifying frameworks for chemical testing and risk assessment. While the details of these frameworks vary, their underlying ideas are similar: researchers link specific molecular changes caused by environmental chemicals with adverse outcomes at the organism level (ie: disease), and then risk assessment is conducted based on the premise that preventing the early molecular disruption will prevent the development of the end-stage adverse event.

While there are practical advantages and real logic to this mechanism-based approach, a new review article published in Carcinogenesis suggests that this strategy may be overly simplistic and could potentially hinder our ability to adequately identify chemicals that contribute to the development of cancer.

This international team of cancer biologists and environmental health scientists organized their discussion around the “Hallmarks of Cancer,” a list of acquired characteristics that commonly occur in cancer (for example: continued growth, resistance to cell death, and tissue invasion). For each key characteristic, they identified typical target sites for disruption as well as environmental chemicals that have been shown to act on those targets. The researchers focused their discussion solely on chemicals that were not already categorized as human carcinogens by the International Agency for Research on Cancer (IARC), and they took careful note of effects observed at low doses. In addition, they specifically mapped connections between different pathways to highlight cases in which alterations leading to a given cancer hallmark could also lead to another.

Their lengthy review provides an important overview of the procarcinogenic effects of numerous common chemicals, but perhaps the most significant conclusion of this work is to emphasize the pitfalls in the status quo for risk assessment. By focusing on categorizing single chemicals as ‘carcinogens,’ we neglect to acknowledge that combinations of chemicals that individually do not meet criteria to be categorized as ‘carcinogenic’ may act in synergistic ways to promote the development of cancer. Even recent efforts to evaluate the effects of chemical mixtures may be inadequate, as they mostly focus on chemicals with common cellular pathways or targets. What about the numerous compounds, as identified in this review, that act on disparate pathways and organs to contribute to a similar disease process in the body?

To address these problems, the authors propose several key principles for an improved framework for cumulative risk assessment, including consideration of the synergistic activity of:

  • chemicals that act via different pathways
  • chemicals that act on different target tissues
  • non-carcinogens that act at low doses to contribute to pro-carcinogenic processes
  • chemicals that are not structurally similar

Carcinogenesis, like many disease processes, is complicated, and identifying the numerous pathways and organs involved is – and will continue to be – an enormous scientific challenge. Slow progress can be made, nevertheless, with a shift towards testing real-world combinations of chemicals and by using the ‘Hallmarks of Cancer’ to guide relevant and appropriate research. New technologies, such as high throughput screening, computational modeling and systems biology-based analysis, can aid in this process. However, the authors stress that traditional in vivo testing still holds an important place in cancer-related research – at least until there is appropriate validation of these emerging tools.

This publication highlights that our current chemical testing and risk assessment system is overly narrow and negates the complexity with which chemicals can interact in the body. We must broaden our approach to acknowledge that distinct chemicals can act in distinct ways at distinct sites – even at low doses – to contribute synergistically to a specific disease process. Reframing our perspective is daunting, and it will emphasize our limited knowledge about the mixtures of chemicals that we are exposed to everyday. But, if we can look up to see the forest, we may begin to make our way towards safer territory.