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How Individual Variability Affects the Toxicity of Chemicals

Toxic Tuesdays

CHEJ highlights several toxic chemicals and the communities fighting to keep their citizens safe from harm.

How Individual Variability Affects the Toxicity of Chemicals

It’s clear that not everyone responds to the same chemical exposures in the same way. There are many examples of this. The most striking is the person who smoked cigarettes for 30 years and never had breathing problems or developed lung cancer.  A major factor in why this happens is “individual variability.”

People process chemicals differently depending on internal factors. There are two major sources of variability in people. The first is variability in the penetration of a chemical to the target organ, referred to as pharmacokinetics. The second factor is the response of the target organ and biological system itself, referred to as pharmacodynamics. Pharmacokinetics is relatively well understood compared to pharmacodynamics.

There are four sources of variability in people: uptake, distribution, metabolism and excretion. Uptake of chemicals through breathing, referred to as respiratory absorption, is mainly influenced by the solubility of the chemical in the blood and its interaction with the respiratory surfaces in the lungs. The solubility of a single chemical in the blood can differ significantly from one person to another. Solubility in the blood can even change in a single person depending on food intake and diet. How much uptake occurs alters the concentration of a chemical in the body which in turn alters its toxicity. Similarly, dermal absorption, or uptake through the skin, depends on the exposed site, the condition of the skin, and the humidity and temperature of the environment. Uptake through the stomach, referred to as gastrointestinal absorption, depends primarily on stomach content.

The distribution of chemicals in the body is also highly variable and depends primarily on body size and composition. Chemicals that are soluble in fat, for example, will be distributed differently in people with different amounts of fat. Distribution is also affected by the degree to which a chemical can bind to molecules, mostly proteins, in the body. The amount of a chemical bound to proteins in a target organ determines how much damage a chemical can cause. Chemicals that are not bound in the body are more easily removed. Chemical binding can be altered if there’s competition for binding sites due to the presence of other chemicals or drugs in the blood system.

Metabolism plays a central role in how the body responds to a chemical and is probably the most important source of pharmacokinetic variability in people. The body has different ways it can interact with or metabolize a chemical. This interaction helps determine the body’s response to chemicals. In some instances, a chemical can become more toxic and in other instances, it can become harmless. Metabolism mainly takes place in the liver but can also occur in the skin and lungs. Metabolism can be altered by several environmental factors. For example, the simultaneous absorption of chemicals in high doses can slow metabolism because of competition for the metabolizing enzyme in the body. Genetic factors also play an important role in metabolizing toxic chemicals. Individual variability in genes results from differences in the DNA sequence of genes (called polymorphisms). These individual differences play an important role in a person’s response to chemicals such as in the development of cancer. Metabolism can also be affected by age and sex, environment, chemical intake, physical activity, protein binding and lifestyle.

Once a chemical has been absorbed, distributed, and metabolized, it will be excreted from the body. The primary way that the body excretes toxic chemicals is through the kidneys. Some excretion may also occur through the lungs, GI track, skin and mammary glands in pregnant women. Renal excretion is influenced by factors such as kidney function, protein binding, urine pH and urine flow, which also varies in individuals. Volatile chemicals, chemicals with a tendency to evaporate, are generally excreted by the lungs. Pulmonary excretion is determined by the same factors that influence pulmonary absorption.

These many sources of variability mean that two people can be exposed to the same concentration of a chemical but absorb, distribute, metabolize and excrete it differently resulting in a different response. This is why scientists and government health officials struggle to explain what will happen to a group of people exposed to the same mixture of chemicals. A person’s response is highly complex and the scientific understanding of how different variables influence toxicity is not well developed. These gaps in our knowledge reflect the many uncertainties in how chemicals produce their toxic effects on the human body.  

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Particulate Matter (PM)

Toxic Tuesdays

CHEJ highlights several toxic chemicals and the communities fighting to keep their citizens safe from harm.

Particulate Matter (PM)

Particulate matter (PM) is a mixture of chemicals, dust, and liquid droplets that can be emitted into the air from automobiles, power plants, construction sites, smokestacks, and fires. When people breathe contaminated air, this PM gets lodged into people’s lungs and bloodstream. This worsens pre-existing lung diseases and can even cause lung disease, heart disease, and lung cancer. PM is categorized based on the size of particles it contains. PM with particles that are up to 10 micrometers in diameter are designated PM10. PM with particles that are smaller – up to 2.5 micrometers in diameter – are designated PM2.5.

The World Health Organization estimates that over 90% of the worldwide population is exposed to PM above the recommended levels, and that air pollution results in more than seven million premature deaths worldwide each year. As with most pollutants, not all populations are exposed to air pollution like PM equally. In the US, Black, Native American, and Latinx communities bear a disproportionate amount of the health and economic burden from PM. For instance, a recent study estimated that Latinx people experience 63% more exposure to air pollution than they are responsible for creating.

In addition to impacts on the lungs and heart, there is evidence that when pregnant people are exposed to PM, there can be dire impacts on the fetus. Studies have found prenatal air pollution exposure impacts cognitive development in school-aged children. However, little is known about effects earlier in development. A new study has found that prenatal exposure to PM, especially during the last half of pregnancy, is associated with cognitive and motor development impairments at two years of age.

The study recruited 161 Latina mothers and their infants from Southern California. It used each mother’s household address and pregnancy dates to conduct mathematical modeling to estimate their exposure to PM while pregnant. Then, when infants were two years old, the researchers conducted clinical assessments to measure their cognitive and motor abilities. The study found that higher PM10 exposure was associated with lower motor abilities. Using mathematical modeling, they determined that higher exposure to either type of PM during mid/late pregnancy (anywhere from the final 1-5 months before birth) was associated with lower cognitive and motor abilities.

As with any observational study, there are limitations to this study. With a relatively small sample size, it is possible that there are developmental effects of prenatal PM exposure that could not be conclusively determined in this study. The study also used location and timing information to estimate mothers’ PM exposure during pregnancy, but did not directly measure this PM exposure. Furthermore, it is unclear if the cognitive and motor deficits seen here will impact infants as they grow up.

Despite the limitations, the findings of this study are valuable. Importantly, Latinx populations are disproportionately exposed to air pollution like PM, but scientific studies rarely focus on them. Conducting a study of exclusively Latinx mothers and infants is crucial to understanding the consequences of racial inequities in exposure to pollution. While the cognitive and motor effects observed in this study may seem small, they make clear that human exposure to PM is dangerous to health and development, and that these dangers of exposure begin before birth.

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Selenium

Toxic Tuesdays

CHEJ highlights several toxic chemicals and the communities fighting to keep their citizens safe from harm.

Selenium

Selenium is a mineral found in most rocks and soil across the globe. It can be extracted and processed from rock for commercial and manufacturing uses. About half of the processed selenium in the world is used in glass production. Another large portion of processed selenium is used in electronics, such as batteries, solar cells, and photoconductors, and the production of rubber, plastics, paints, and inks.

Selenium can be released into the environment via the manufacturing or disposal process, thereby entering water and topsoil. People can then become exposed by drinking selenium-contaminated water or eating contaminated agricultural products. Selenium also bioaccumulates in fish, meaning people may be exposed to harmful levels of selenium even if they do not live near a manufacturing or disposal site. Short-term oral exposure to high levels of selenium can cause nausea and vomiting. Long-term oral exposure can cause a disease called selenosis, which can include gastrointestinal dysfunction, neurological dysfunction, hair loss, and sloughing off nails. In extreme cases, selenosis can even cause cirrhosis and death. Selenium dust can also be released into the air when burning oil or coal. This can cause coughing, bronchitis, and irritation of the respiratory tract, which can make it difficult to breathe.

While trace amounts of selenium are required to maintain human health, short- or long-term exposure to high amounts of selenium are dangerous. There are many examples from around the world of people, fish, and birds being poisoned by selenium. With its diverse array of commercial and manufacturing uses, it is crucial that protections be put in place to ensure that people are not exposed to it.

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Ethlybenzene

Toxic Tuesdays

CHEJ highlights several toxic chemicals and the communities fighting to keep their citizens safe from harm.

Ethylbenzene

Ethylbenzene is a colorless flammable liquid that comes from coal tar and petroleum. It is primarily used to synthesize chemicals that are used in plastics. Ethylbenzene can also be used in fuels and injection fluid, which is used to release natural gas from the ground. It has industrial uses in solvents and pesticides and can also be found in consumer products like paint and ink. Spills and waste disposal from factories that use ethylbenzene often enter the water and soil. Burning oil, gas, coal, and cigarettes can release ethylbenzene into the air. Inhalation of this contaminated air is the primary path of exposure.

Brief inhalation of air contaminated with ethylbenzene can cause eye and throat irritation and dizziness. Little else is known about the human health effects of short- or long-term exposure to the chemical. In scientific studies of laboratory animals, short-term exposure has been shown to cause permanent hearing loss; long-term exposure has been shown to cause kidney damage too.

The International Agency for Research on Cancer says that ethylbenzene is a possible human carcinogen, meaning it might cause cancer in humans. While more studies could be done to better understand the effects of exposure on humans, it is clear ethylbenzene is a biologically dangerous chemical, and there should be protections in place to ensure that people are not exposed to it.

 

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Benzo(a)pyrene (BaP)

Toxic Tuesdays

CHEJ highlights several toxic chemicals and the communities fighting to keep their citizens safe from harm.

Benzo(a)pyrene (BaP)

Benzo(a)pyrene (BaP) is a compound in a group of chemicals called polycyclic aromatic hydrocarbons (PAHs). PAHs like BaP are formed in the incomplete burning of coal, oil, gas, or other organic matter. Once formed, they can enter the air, water and soil. The most common way people are exposed to PAHs is by inhaling contaminated air. Vehicle exhaust, wood smoke, asphalt paving and agricultural burning can expose people to PAHs like BaP.

Exposure to BaP for even short periods of time can affect blood cells, leading to anemia and immune system defects. Exposure for long periods of time can affect function of the reproductive system. In studies of laboratory animals, prenatal exposure to BaP impaired learning and memory of offspring.

The most widely known effect of BaP exposure is cancer, and links between BaP and cancer have been known since the 1970s. BaP is one of many components of tobacco smoke that can cause lung cancer. BaP is dangerous because the body converts it into other compounds that can permanently change our cells’ DNA. This can cause cells to function improperly leading to cell death, abnormal cell growth, tissue damage and/or cancer.

CHEJ has previously written about PAHs here.

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Exposures to Chemical Mixtures Matter​

Toxic Tuesdays

CHEJ highlights several toxic chemicals and the communities fighting to keep their citizens safe from harm.

Exposures to Chemical Mixtures Matter

Considering cumulative exposures to low levels mixtures of chemicals is an enormous challenge when evaluating the toxicity of chemicals. Neither the EPA nor ATSDR have guidance on how to evaluate exposure to multiple chemicals simultaneously, or cumulatively over time. The EPA does have its Risk-based Screening Levels (RSLs) that provide some guidance on risk estimates, but these values only consider chemicals in isolation, or when exposed to one chemical at a time. This limitation has begun to be recognized as a fundamental weakness in the way research is done on the toxicity of chemicals. Testing one chemical at a time is not sufficient nor appropriate for evaluating public health risks when people are exposed to multiple chemicals at the same time, or cumulatively over time.  

This limitation was highlighted when a group of 350 cancer research scientists came together in Halifax, Nova Scotia to address the question of continuous multiple chemical exposures and the risks these exposures pose. Referred to as the Halifax Project, this effort merged two very distinct fields – environmental toxicology and the biological mechanisms of cancer – and provided the opportunity for researchers to look at the diversity of environmental factors that contribute to cancer by examining the impact that exposure to very small amounts of chemicals can have on various systems of the body.

These scientists looked at whether everyday exposures to mixtures of commonly encountered chemicals have a role to play in cancer causation. The researchers began by identifying a number of specific key pathways and mechanisms that are important in the formation of cancer. Then they identified individual (non-carcinogenic) chemicals that are commonly found in the environment that had some potential to disrupt these systems. A total of 85 environmental chemicals were identified.

The authors found that 59% of these chemicals (50/85) had low dose effects “at levels that are deemed relevant given the background levels of exposure that exist in the environment.” They found that only 15% of the chemicals reviewed (13/85) had a dose-response threshold and that the remaining 26% (22/85) could not be categorized due to a lack of dose-response information. The authors concluded that these results help “to validate the idea that chemicals can act disruptively on key cancer-related mechanisms at environmentally relevant levels of exposure.”

This is an important observation because it challenges the traditional thinking about how cancer forms in the body. It challenges the notion that all cancers share common traits (considered the “hallmarks of cancer”) that govern the transformation of normal cells to cancer cells. The authors also discuss how the results in this paper impact the process of risk assessment as even its most sophisticated model fails to address continuous exposures to mixtures of common chemicals. 

The authors concluded that “the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies.” In other words, exposure to multiple chemicals at low doses, considered individually to be “safe,” could result in various low dose effects that lead to the formation of cancer. This is a remarkable observation and conclusion. It is also an important advance in the understanding of the risks chemicals pose to society. It also highlights how surprisingly little is actually known about the combined effects of chemical mixtures whether on cancer related mechanisms and processes or on adverse effects in general.  

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Total Petroleum Hydrocarbons (TPHs)

Toxic Tuesdays

CHEJ highlights several toxic chemicals and the communities fighting to keep their citizens safe from harm.

Total Petroleum Hydrocarbons (TPHs)

Total petroleum hydrocarbons (TPH) are a family of hundreds of chemicals that come from crude oil. When crude oil is spilled during extraction or processing into petroleum products, TPHs can contaminate the environment. Because TPHs contain so many chemicals, it can be impractical or impossible to measure each individual chemical. Instead, total concentrations of TPHs are measured at contamination sites. Upon contaminating soil, some TPH components will remain there for a long time without breaking down. Upon contaminating water, some components will form films on the surface while others will sink to the bottom. Touching contaminated soil or drinking contaminated water can lead to exposure to TPHs. Because many products and gasolines are derived from crude oil, almost everyone has some exposure to TPHs even in the absence of a chemical spill. For instance, breathing the air at gas stations or using certain pesticides can cause exposure to TPHs.

Exposure to TPHs can have effects on the nervous system, causing headaches, dizziness, or numbness in the extremities. Some TPH chemicals can also affect the blood, immune system, respiratory system, and skin. In laboratory studies on animals, TPH exposure was also found to affect liver function, kidney function, and fetal development. Furthermore, at least one TPH chemical – benzene – is known to cause cancer in humans. Despite known health effects of exposure to TPHs, and the potential for synergistic effects of simultaneous exposure to multiple TPH chemicals, there are no federal regulations specific to TPHs.

CHEJ has previously written about the health effects of some chemicals commonly found in TPH and communities that have been exposed to them: benzene, naphthalene, toluene, and xylene.

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Glycophosate

Toxic Tuesdays

CHEJ highlights several toxic chemicals and the communities fighting to keep their citizens safe from harm.

Glyphosate

Glyphosate is a chemical found in weed killer products such as RoundUpTM used on farms and home lawns. It gets absorbed by plant leaves, stopping plant growth within hours. Because of its effectiveness, glyphosate is found in widely used products that are easily obtainable. It is used all over the United States, but its highest concentrations are in the Midwest and Plains states. When glyphosate-containing weed killers are sprayed to kill plants, it can be inhaled and get on the skin. This can cause skin irritation and respiratory effects. People frequently working with glyphosate may be more likely to develop these respiratory effects. In scientific studies on animals, exposure to glyphosate during pregnancy caused developmental defects in the resulting offspring. Furthermore, there is concern that when combined with other chemicals found in weed killer products, glyphosate may have increased toxicity on humans.

Whether or not exposure to glyphosate increases the risk of cancer is inconclusive. The US EPA classifies it as not likely to cause cancer; however, the International Agency for Research on Cancer (IARC) concluded that it probably does. There have been allegations that large agrochemical corporations that use glyphosate in their products have close relationships with the governmental organizations that conduct the studies regarding glyphosate’s health risks. While more studies and risk assessments may need to be done to be certain of the risks, it is crucial that these studies are done transparently and without bias to protect and inform the public.

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Transgenerational Toxicity

Toxic Tuesdays

CHEJ highlights several toxic chemicals and the communities fighting to keep their citizens safe from harm.

Transgenerational Toxicity

While getting cancer, liver disease or central nervous system damage is often associated with exposure to toxic chemicals, one of the most sensitive targets of toxic chemicals is the reproductive system. This has long been recognized for over 50 years (123). In recent years however, research has shown that toxic chemicals can not only directly affect the reproductive system of both women and men, but that these effects can be passed on to the next generation and can even skip a generation. The impact of toxic chemicals on children with no direct exposure to these chemicals is known as a transgenerational effect.

A recent review paper reported that research on chemical toxicity, early life nutrition, smoking and radiation found evidence of harm even in offspring with no direct exposure to specific contaminants. This paper pointed to groundbreaking research at Washington State University that helped establish the principle of transgenerational toxicity by showing that the effects of toxic chemicals can extend even to the third generation of offspring. Other review papers have found a growing body of evidence from epidemiological studies that suggests that environmental exposures early in development have a role in susceptibility to disease in later life and that some of these effects seem to be passed on through subsequent generations (67).

One important study that made this clear was a follow-up study on the residents of Love Canal in Niagara Falls, NY. This study, conducted by the New York State Department of Health (DOH), found that maternal exposure to chemicals from the Love Canal landfill was associated with an elevated risk of bearing a child with an adverse reproductive outcome. The researchers found that women who lived in the designated emergency zone while pregnant prior to the time of evacuation had a higher risk of having a preterm birth compared to women from other regions of the state. This effect was statistically significant.

There was also a greater than expected frequency of congenital malformations among Love Canal boys born from 1983 to 1996. These birth defects occurred in infants born to mothers who previously lived at Love Canal. The rate of these birth defects was about 50% higher than in boys born to mothers who lived in upstate NY. In addition, the ratio of male to female births was lower for children conceived at Love Canal. Lastly, women exposed as children had an increased risk of giving birth to a low weight baby.

These findings are consistent with the initial findings at Love Canal that led to the evacuation of the community in 1978 and 1980. The initial findings identified lower birth weight and increased congenital birth defects in infants, but were limited in defining the risk of adverse pregnancy outcomes because of small sample sizes.

This study is extraordinary because it looked at the reproductive outcomes of women after their exposure had stopped compared to other studies which typically evaluate health effects at the time when exposures were ongoing. In some cases, exposures to Love Canal chemicals occurred only when the women were children! These remarkable findings point out the subtle impact of exposure to toxic chemicals. They are a red flag for health concerns – especially for women of child bearing age – at other contaminated sites across the country. This study also highlights how little we really know about low level exposures to toxic chemicals.

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Polybrominated diphenyl ethers (PCBEs)

Toxic Tuesdays

CHEJ highlights several toxic chemicals and the communities fighting to keep their citizens safe from harm.

Polybrominated Diphenyl Ethers (PBDE)

Polybrominated Diphenyl Ethers (PBDE) are chemicals that are flame retardants – meaning they are added to different materials to make them less susceptible to fires. PBDEs are found in various everyday materials, such as furniture padding, computers, rugs, and electrical wires. They are a synthetic (not naturally found in the environment) subset of the organobromine compounds, chemicals where a carbon molecule is bonded to a bromine molecule. There are 209 different forms of PBDEs, which vary based on what the carbon-bromine structure looks like.

PBDEs were discovered in the 1970s, and since then, several of them have been phased out of production (PentaBDE and OctaBDE), but other versions (such as DecaBDE) are still being manufactured. While some states, such as California and Washington, have banned specific forms of PBDEs from production, there is no national restriction on the production of this chemical as of 2023. It’s also important to note that even for PBDEs that have been banned or phased out of production, the waste from production and manufacturing remains in the environment and causes harm.

The lack of national attention to this class of chemicals is concerning because of the mounting evidence that PBDEs have negative impacts on human health. For example, these chemicals are thought to be endocrine-disrupting. The endocrine system, which oversees the regulation of hormones, is vital to human health. When this system is damaged, it can cause various adverse health effects, such as cancer, reproductive damage, and neurological damage. A case-control study found that exposure to PBDEs was associated with an increased risk of breast cancer among post-menopausal women. Another study found that the BDE-28 compound was associated with an increased risk of papillary thyroid cancer. As for reproductive health, a study on infants reported that pregnancies that had PBDE chemicals in the umbilical cords, those infants were more likely to have lower birth weights. And a chemical that causes fetal abnormalities is called a teratogen, although PBDE does not carry this classification by the Environmental Protection Agency. Evidence of neurological damage has also been in animal studies, where PBDE was found to cause neurotoxic effects on memory, attention, and leaning ability.

Exposure to PBDEs during pregnancy is only one route of exposure to this chemical. Because PBDEs decompose slowly in the environment, they bioaccumulate and build up in the food chain. Fish and other marine life are especially prone to bioaccumulation. Thus, PBDE contamination could be of concern for people who consume a lot of seafood or rely on it as their primary protein source. Another way that people can be exposed to the chemicals is through water. PBDE waste can seep through the ground and contaminate the groundwater sources. Another exposure route, which accounts for an estimated 80% to 90% of exposure for the population, is inhaling contaminated dust particles. For example, PBDE can be found in the dust that accumulates in homes. One study found that individuals who had higher levels of PBDE in the dust at their houses had higher levels of the chemical in their blood serum levels.

PBDEs are considered persistent organic pollutants (POP), and many communities are fighting against this contamination in their backyards. For example, the Alaska Community Action on Toxins (ACAT) has been advocating for years to ban the use of PBDEs in the state. Another group that has been advocating for the ban on PBDEs are first responders, specifically fire-fighter organizations. When blood samples were taken from firefighters, they had brominated dioxins and furans in their bloodstreams. Fire fighters are more exposed to these chemicals because when a house fire occurs, all of the products that have PBDEs in them, such as furniture upholstery, burn up and release these toxic chemicals into the air that the first responders breathe in.

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