Subsection 4, Toxicity Assessments (Chapter 14 of this week’s reading) describes the risk assessment stage whereby toxicities are defined for chemicals of concern. This subsection discusses the mathematical relationship between a particular dose of a chemical and the extent of the human response. Early Roman physician, Paracelsus first coined the phrase: “the dose makes the poison,” which was intended to show that all things can be poison and what distinguishes therapeutic use of a compound from a toxic effect depends upon dose strength. Until recently, the slope of this relationship was determined to be a positive slope—the more you ingest, the greater the effect. When human responses to a toxic chemical are uncertain, government risk assessors rely on findings from animal studies and build in safety factors to account for more vulnerable human populations, uncertainties inherent in extrapolating human effects from animal studies, and/or reliance on in vitro studies. For non-carcinogens, the protective factor is often two factors of ten. For carcinogens, models assume the studies apply at the 95% confidence level. Using these models, toxicologists set exposure limits often starting at the highest dose and then progressively retest at lower doses until reaching the point at which the effects are no longer seen. The endpoint of no effects is termed the “no observed adverse effect level” or NOAEL. Combining the use of safety factors and NOAEL, scientists determine the Reference Dose to determine the safety of human exposure to toxic chemicals. Besides ISIS databases, the Agency for Toxic Substances and Disease Registry (ASTDR) also lists handy toxicological profile readily available on their website.
There are several problems in this approach, but Chapter 14 discusses only one—synergistic chemical interactions. Synergistic effects occur when the effects of substances A and B taken together are higher than simply adding the effects together—implying that somehow calculation of risk needs to consider combinations of chemicals. Determining synergistic effects is often difficult to accomplish because of many unknowns, multiple different combinations of synergistic chemicals, and the time/expense of conducting dose-response experiments. One complication that Chapter 4 fails to mention is extensive research in recent years challenges the assumption of positive slope dose-response curves for all chemicals. Positive slope curves are monotonic curves and can either be linear or non-linear. For human exposure to chemicals that contain hormonally active compounds, a very different dose-response curve has been discovered to hold true in recent years. It is a non-monotonic curve that has both positive and negative slopes and can either be a U-shaped curve or an inverted U-shaped curve (see Figure 1).
(Figure 1.) Source: (Myers & Hessler, 2007)
As discussed by Myers, Zoeller & von Saal (2007), the use of high dose level testing to predict low dose human responses is not valid for endocrine disrupting chemicals (EDCs). Examples of EDCs include the plastic monomer bisphenol A (BPA), dioxins, PCBs, DDT/DDE, phthalates, alkylphenols and phytoestrogens. If effect, the low dose hormonally active compounds have their most powerful effects at dose levels far below the NOAEL. For example, the prescription drug Tamoxifen, used to treat women with breast cancer, stimulates breast cancer at low doses but inhibits the disease at higher doses. These authors also state that research conducted in the past two decades has revealed that many of the EDCs are widespread in the environment and commonly found in people. Yet the toxicology studies have missed effects that happen at extremely low doses (i.e. picomolar parts per trillion). Moreover, not only are higher impacts seen at ultra low doses, but the effects may be entirely different. For example, high exposures to phthalate diethylhexylphthalate (DEHP) can result in liver failure, while exposures to DEPH that are 1/1000th of the current safety standard results in allergic reactions.
The consequences of missing non-monotonic effects are not insignificant. For EDCs commonly found in the ambient environment (phthalates, for example) evidence demonstrates that prenatal exposure of males in utero can now be seen as they become infants and children. These effects include reproductive malformations (smaller penises, undescended testicles), smaller gestational age at birth (both genders), premature menarche, and respiratory symptoms in both genders (rhinitis, eczema, asthma) (Swan, 2008). Swan also states that animal testing of phthalates used much higher doses than those seen in ambient human populations. Moreover, phthalates have traditionally been tested as singular insults when in reality, humans are exposed to multiple phthalates simultaneously. However, in experiments with rats, exposure to multiple phthalates was shown to have additive synergistic effects.
In a review of the many health risks incurred from exposure to a variety of EDC chemicals, Yang, Park, & Lee (2006) discussed many human effects of EDCs, specifically: immune and hormonal disorders (i.e., compromised immune function, higher rates of Type-2 diabetes), reproductive disorders (i.e., precocious puberty, polycystic ovary disorder, low sperm counts and qualities, male reproductive tract abnormalities, altered birth sex ratios), and neurobehavioral disorders (such as lower IQ, memory changes, motor impairments, and thyroid disorders).
In light of findings of non-monotonic effects of EDCs, one might wonder whether EPA’s protective nature of calculations used in evaluating toxicity assessment is truly sufficient. For example, Soto, Vandenbert, Marrini & Sonnenschein (2007) discuss how rat studies demonstrated that fetal exposure to BPA resulted in higher incidences of breast cancer when such rats reached adulthood. Epidemiological studies based on the toxicological assumption that the dose makes the poison will not find these effects. A whole new paradigm of assumptions must be incorporated to shift toward greater acceptance of non-monotonic dose-response curves to more effectively protect human health from these ubiquitous EDCs. Moreover, tests need to be conducted on synergistic effects from combinations of EDCs commonly seen among human populations to increase the validity and applicability of study findings.
In recent testimony before Congress, Dr. Linda Birnbaum, Director, National Toxicology Program and Director, The National Institute of Environmental Health Science, both at HHS (2010) elucidated on the urgent need for additional research to incorporate new tools from biomedical science (i.e. genomics, proteomics, metabolomics, informatics, and computational biology) to establish a new framework for toxicity testing for chemicals that will improve risk assessment and management for EDCs, such as BPA. So I am hoping that incorporating these new tools will result in improved paradigms for toxicity testing that are cheaper/quicker, more effective, and more closely identify appropriate dose-response effects.
References:
Burnbaum, L.S. (2010). Testimony before the US House of Representatives, Committee on Energy and Commerce, Subcommittee on Health, April 22, 2010. The environment and human health: The role of HHS. Accessed on September 4, 2010 from http://www.hhs.gov/asl/testify/2010/04/t20100422a.html
Myers, P., Hessler, W. (2007). Does the ‘dose make the poison.’ Environmental Health News. April 30. 1-6.
Peterson, J, Zoeller, R.T., Von Saal, F.S. (2009). A clash of old and new scientific concepts in toxicity, with important implications for public health. Environmental Health Perspectives. 117(11). Retrieved on September 4, 2010 at http://ehsehplp03.niehs.nih.gov/article/fetchArticle.action;jsessionid=3ACF3993995ED5BBD7879F4F3A5CA7D8?articleURI=info%3Adoi%2F10.1289%2Fehp.0900887
Soto, A.M., Vandenbert, L.N., Marrini, M.V., Sonnenschein, C. (2007). Does breast cancer start in the womb? Basic & Clinical Pharmacology & Toxicology. 102:125-133.
Swan, S.H. (2008). Environmental phthalate exposure in relation to reproductive outcomes and other health endpoints in humans. Environmental Research. 108:177-184.
Yang, M, Park, M.S., Lee, H.S. (2006). Endocrine disrupting chemicals: human exposure and health risks. Journal of Environmental Science and Human Health, Part C. 24: 183-224.
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