An Update on East Palestine: Dioxin Exposure in Humans, A Review of the Literature
Following the dumping and subsequent burning of 68,000 pounds of vinyl chloride, an issue of dioxin exposure has become relevant to the people of East Palestine, this is a review of the literature.
Abstract
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a persistent organic pollutant (POP) and known human carcinogen and teratogen. The full extent to which TCDD affects the human body is currently unknown, although it is still regarded as the most dangerous toxin known to man. The immediate exposure effects of TCDD can often differ based on dose amount, but it is common to find exposed individuals suffering from nausea, headache or migraine, dizziness and vomiting, as well as non-specific gastrointestinal discomfort or pain and potential impairment of liver function. Overall, the case reports of humans exposed to TCDD in both low and high quantities find that the integumentary system, nervous system, endocrine system, immune system, cardiovascular system and specific brain functions were directly impaired or harmed. Due to the nature of the derailment, and subsequent chemical burning, it is important for East Palestine residents to understand the potential impact of TCDD exposure on the body.
Introduction
The mechanisms by which TCDD exposure affects the human body’s ability to perform natural functions are well documented. TCDD binds to the Aryl hydrocarbon Receptor (AhR) causing AhR activation, which induces a host cell response through immunomodulation.[3] Furthermore, TCDD exposure drastically and significantly modified cytoskeletal organization,[4][Fig. 3] a mechanism by which viruses can facilitate viral replication.[4][5][6] The ability for dioxin to suppress the immune system, as well as enhance viral replication is directly associated with increased susceptibility of viral infection as well as an increased mortality rate among those infected.[3][7][8][9] Differences in metabolism, body fat or hormone-related factors may play a role in findings that suggest higher TCDD exposure and more persistent TCDD levels are found in women as opposed to men.[10][11] Elevated TCDD levels in women may contribute to adverse reproductive and developmental outcomes, including preterm birth, spontaneous abortion and an increased teratogenic and mutagenic risk.[10][12][13][14] The induction of cytochrome P-450 1A1 (CYP-1A1) mRNA is one of the known causes of carcinogenic effects following dioxin exposure. This particularly sensitive endpoint is measurable after a single dose of 100 picograms of TCDD per kilogram of body weight in rats.[15] Studies for the exact endpoint dosage in humans must be done to determine what level creates carcinogenesis in humans, although the WHO’s guidance on a safe dosage of 10 picograms of TCDD per kilogram of bodyweight and day was based on extrapolated no-observed-adverse-effect level (NOAEL) data of 100 picograms of TCDD per kilogram of bodyweight and day for humans. This described low-dose threshold for safety is disputed. Unfortunately, the shape of the dose–response curve in the low dose range is unknown and, in particular, we do not know whether or not a threshold for the carcinogenic effect exists.[16] TCDD half-life in humans is currently a highly complex and debated topic. The half-life of the substance varies from person to person, dose amount and between gender, but it has been observed to be at least 7 years in men and 9 years in women.[10][11][17] A recent finding suggests a link between dioxin exposure and heart disease, finding several increased rates of ischemic heart disease in cohorts spanning different countries among different exposure levels.[18] The main method by which humans are exposed to dioxin is through food consumption.[19][20] The amount of dioxin present in food globally has been on a decline since the 1980’s, but data on the consumption of food containing dioxin in the United States is limited and requires further monitoring and research.[20]
Immediate and Observable Health Effects
Chloracne is accepted as the leading side effect of high TCDD exposure. As a result, chloracne is used as a marker in patients exposed to TCDD to indicate high exposure, and thus studied at length.[38] According to research done by N. Marinković et al. short-term exposure to high levels of TCDD impairs liver function.[44] A. Geusau found that patients who suffered high exposure had nonspecific gastrointestinal pain.[2] W. Piper et al. may have found the mechanism by which dioxin caused this pain and discomfort. The study found that in rats, absorption from the gastrointestinal (GI) tract ranged from 66-93 percent.[45] Finally, the New Jersey Department of Health and Senior Services: Hazardous Substance Fact Sheet states that direct contact with dioxin can irritate and burn the skin and eyes. Exposure can cause headache, weakness, dizziness, nausea and vomiting, with high enough levels of exposure causing damage to the nervous system, which can cause personality and mood changes, pain in the legs, and numbness.[1] Understanding the immediate risks of TCDD exposure is important in determining whether or not residents of East Palestine were exposed to unsafe levels, as well as workers tasked with cleaning up and burning the chemicals at the site of the derailment.
Immunosuppression
The method by which TCDD binds to the AhR causing AhR activation leads to inflammation as well as decreased antibody production, TCDD exposure also induced an increase in pulmonary neutrophilia in mice.[21][8][24] The effects of dioxin on the body’s immune response following influenza virus infection are thoroughly documented. T. Warren et al. found that a single oral dose of 1–10 μg TCDD/kg caused death in mice infected with a non-lethal influenza A virus.[9] J. Thigpen et al. concluded that TCDD exposure in mice resulted in a significantly higher rate of mortality with a shorter incubation period.[7] It is thus hypothesized that TCDD exposure coupled to viral infection may induce a variety of biological effects also depending on the viral subtype.[3] R. Hoffman et al. found findings suggesting that long-term exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin is associated with depressed cell-mediated immunity, although the effects have not resulted in an excess of clinical illness in the exposed group. Further studies are indicated to elucidate the pathophysiology and clinical significance of these immunologic findings.[32]
The relationship between dioxin exposure and human immunodeficiency virus-1 (HIV-1) is extremely pertinent. Pokrovsky et al. found that in vitro, in human leukemia T cells exposed to TCDD there was a significant increase of HIV-1 virus production.[22] Gollapudi et al. found that exposure to dioxin triggers HIV-1 gene expression, causing increased production of HIV in chronically infected promonocytic U1 cells. The study found that TCDD enhanced NF-Kappa B activity and stimulated the production of tumor necrosis factor alpha in U1 cells, as a result, authors suggested the potential for molecular alterations in cells exposed to dioxin.[23] It has been concluded that exposure to polyhalogenated aromatic hydrocarbons, such as TCDD, may contribute to the clinical development of AIDS.
F. Fiorito et al. (2017) concluded that dioxin, by acting in an orchestrated manner, suppresses immune response thereby leading to an increased susceptibility to infectious agents. The presence of dioxin is able to modify the replication of several viruses. TCDD-mediated AhR activation can act on host cell responses to influenza A viruses through immunomodulation. Moreover, dioxin enhances viral replication, precisely in CB3, HIV-1, CMV, HSV-II, or in BHV-1 infections. The activation of the AhR by TCDD can be associated with decreased host response and reduced survival in vivo, and with the onset of viral infections in vitro. On the whole, the available data support the concept that TCDD exposure may act as a risk factor for the progression of viral diseases. However, further studies are required to better characterize the biological effects of dioxin on viral diseases in humans.[3]
Carcinogenicity
It is widely accepted that TCDD is a human carcinogen due to the mechanism by which dioxin binds to the AhR causing AhR activation and inducing cytochrome P-450 1A1.[19] M. Hooived et al. found that in a Dutch cohort exposed to TCDD, the cancer mortality rate ratio was 4.1 compared to the control. This jumped to 7.5 for respiratory cancer, although smoking habits cannot be ruled out as a contributing factor in this instance, other findings have also suggested that TCDD exposure plays a particular risk factor in developing respiratory cancers.[34][35][37] Similarly, P. Bertazzi et al. found that in a male population cohort following the Seveso disaster, all-cancer deaths were significantly in excess after 15 years.[35] This matched findings suggested by another long-term, high exposure, male-occupant cohort, which concluded that dioxin was responsible for the development of testicular cancer, thyroid cancer and other cancers of the endocrine glands. Successfully leading to a 9 fold increase in excess mortality due to cancer after a 10-19 year period following exposure.[37] Ultimately, the International Agency for Research on Cancer (IARC) has classified TCDD as a Group I carcinogen, indicating there is no safe dose for dioxin exposure.[39]
Teratogenicity and Infertility
Teratogens are classified as an agent or factor that causes malformation of an embryo. Due to the nature of toxic exposure, it is difficult to perform studies on the teratogenicity of TCDD in humans, although it is widely accepted to be a teratogenic agent. X. Pan et al. concluded in their systematic review on TCDD exposure and birth defects that low birth weight (LBW) was directly associated with food-related dioxin exposure. Maternal exposure to solid contaminants dioxin was associated with birth defects. Although, the association between exposure to dioxin-related toxicants and other adverse pregnancy outcomes in humans was inconclusive, with the exception of Agent Orange (TCDD).[14] B. Eskenazi et al. found that dioxin exposure had a causal link to birth defects in animals, although studies in humans had small sample sizes and varying results.[12] Y. Tao et al. found a mechanism by which TCDD creates cleft palate in developing embryos. Through suppression of the Octamer-binding transcription factor 4 (Oct4), TCDD may promote the apoptosis of palatal mesenchyme, inducing cleft palate. The authors, however, agreed that the mechanisms of TCDD-affected cleft palate formation remained not fully explored, and thus more research is required.[31] A. Ngo et al. found in their systematic review of the literature on dioxin exposure through Operation Ranch Hand that the individuals most affected by birth defects were civilians directly sprayed in affected areas. The strength of the association between exposure to Agent Orange/dioxin and birth defects in the Vietnamese population was substantially greater than that in the non-Vietnamese populations. This observation is consistent with the finding that higher dioxin concentrations were found in the Vietnamese population in affected areas than in US Vietnam veterans.[25] These findings may suggest that exposure level and the method of exposure directly affects the rate of birth defects, further supporting the need for proper testing of air, soil and water quality before other tests are performed.
Dioxin may also play a factor in male infertility rates. P. Mocarelli et al. found that 71 men exposed to TCDD between ages 1-9 had a significant effect on semen quality measured 22 years later. Indeed, significant decreases in sperm count, progressive sperm motility, and total number of motile sperm were observed relative to the comparison group. This finding suggests that dioxin, even with an observed shorter half life in younger patients, still has lifelong impact for any individual exposed in high enough doses.[26] Interestingly, C. Lawson et al. found that paternal exposure to TCDD did not negatively impact birth weight nor result in a statistically significant effect of birth defects. Suggesting that paternal exposure alone to TCDD is not a risk factor during pregnancy.[27]
TCDD exposure has been linked as a causality factor for endometriosis (a condition that leads to infertility in women).[28][29] A. Mayani et al. established the basis for a correlation between TCDD exposure levels and an 18% rate of endometriosis, as opposed to a 3% rate of endometriosis in the control group.[28] P. Simsa et al. produced the first ever case-control study that found exposure to dioxin-like-compounds (DLC) created a statistically significant increase in endometriosis, finding women exposed to DLC are 2.5 times more likely to have endometriosis and five times more likely to have severe endometriosis than women with lower concentrations of DL-compounds.[29] These results come after a critical review of the literature from P. Simsa et al. (2007) was published finding that a statistically significant link between dioxin and endometriosis was not present.[30] The results of P. Simsa et al. (2010) may provide information to come to the conclusion dioxin exposure in women leads to an increased risk of infertility, although more studies on the subject are necessary.
Cardiovascular Disease
Plausible mechanisms exist for an effect of TCDD on cardiovascular disease, primarily by an alteration of lipid metabolism. K. Steenland et al. found that TCDD exposure is associated with highly elevated rate ratios for mortality from ischemic heart disease (IHD).[18] J. Vena et al. found that in a multi-country cohort, the rate ratio of IHD was 1.67, though they indicated that more studies should be done to establish a causal link.[33] M. Hooived et al. found that TCDD exposed patients in a Dutch cohort had an elevated rate ratio of 1.8.[34] P. Bertazzi et al. found that regardless of dietary and smoking habits among exposed and unexposed populations, circulatory disease mortality (chronic ischemic heart disease in particular) was elevated in males in the early post-accident period.[35] O. Humblet et al. found there is sufficient data to suggest that TCDD exposure is associated with increased risk of mortality from both IHD and all CVD, although because of the nature of these studies, uncontrolled confounding by other risk factors for CVD cannot be ruled out as a contributor to the association.[36]
Environmental and Agricultural Implications
Dioxin is classified as a persistent organic pollutant, meaning it can remain present in the environment for extremely long periods of time. T. Tuyet-Hahn et al. found that the impacts on the environment can be profound, once released into the atmosphere, dioxin often binds to other particulates such as incinerator ash. In this case it is shielded from photo-degradation and is able to stay suspended for a long period of time before settling.[40] This further leads to the conclusion that proper air safety testing is required to conclude that East Palestine and the surrounding area are safe. The Center for Health, Environment & Justice found that in water, dioxin accumulates in the bottom mud and sediments of rivers, lakes, and the ocean. As a result of this accumulation, dioxin concentration in fish is 100,000 times higher than that in the surrounding environment. Dioxin in soil particles or dust attaches to grass, vegetables and crops. Animals that feed on contaminated grass such as cows, buffalo, and goats, and other free ranging animals such as ducks, chicken and wild goose that are raised in areas containing contaminated soil can concentrate dioxin in their meat.[41] This continues to support the conclusion that the majority of dioxin exposure in humans is done through contaminated food consumption.[42] Although air quality and testing should be the first and foremost step in ensuring the safety of East Palestine residents, it is equally as important to scan the surrounding soil, water and subsequent food supply in East Palestine, which could be contaminated with dioxin levels much higher than what is deemed safe, although the idea that there is a “safe level” of TCDD exposure in humans is highly debated, meaning any conclusive evidence of exposure should be taken very seriously.[39] J. Huwe found that one way to ensure that foods are low in dioxins and remain low is through routine monitoring. Monitoring programs provide an estimate of the background levels found in different food groups. Once a baseline has been established, following trends in dioxin levels can indicate problems or progress.[20]
Conclusion
Although dioxins are the most extensively studied class of environmental contaminants, many uncertainties surround the evaluation of the margin of safety between current background exposures and the level of exposure required for expression of adverse effects. A conservative approach to risk assessment suggests that the margin of safety is narrow and that efforts to reduce background human exposures are desirable.[43] Research suggests that exposure to TCDD in any quantity can lead to adverse health effects.[39] The release of dioxin into the air following the burning of chemicals such as vinyl chloride in East Palestine is already a known fact, but the extent to which dioxin will affect residents in the coming days, months and years is still unknown. This problem has potentially sweeping impacts across the country, as dioxin is persistent throughout the environment. When produced in massive quantities as well as being aerosolized, dioxin has the chance to spread throughout a population.[25] The nature of the toxin requires careful consideration of PPE during cleanup. Among residents of the town, precautions should be taken to minimize exposure, namely avoiding air directly near the burn site, water from the surrounding area and food produced and manufactured in the area. It is of utmost importance that both the EPA and Norfolk Southern provide conclusive evidence that TCDD exposure was properly mitigated and that all cleanup workers involved are properly informed of their exposure levels, as well as provided with the proper protective equipment to avoid high levels of exposure.[1] Residents of the town should be informed of the level to which they were exposed, as well as the potential dangers of TCDD exposure.
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