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EH705: Problem Set 3 20 Points 1. (5 pts) Human exposure to arsenic is extensive due to its leaching into ground water. According to the USGS, “ Arsenic release from iron oxide appears to be the most common cause of widespread arsenic concentrations exceeding 10 µg/L in ground water” ( http://water.usgs.gov/nawqa/trace/pubs/gw_v38n4/ ). To find out more about arsenic, 1) Go to EPA’s IRIS website ( https://www.epa.gov/iris ) and read “Key IRIS Values” tab for arsenic (feel free to check out the other tabs too!) Under the “Assessments” section of the main page, click on “Browse A to Z list of chemicals.,” then find arsenic under the “A’s.” 2) Read, Nicole, W. 2013. Evolutionary selection for arsenic resistance. Environ Health Perspect 121: a31. https://ehp.niehs.nih.gov/121-a31/ Let’s consider some aspects of arsenic’s biotransformation and carcinogenicity. a. (1 pt) How do human cells typically biotransform arsenic? Which type of reaction is likely to generate a more toxic form of arsenic? Identify one of two most toxic arsenic metabolites generated by human cells. Human cells biotransform arsenic via reactions such as oxidation reduction, methylation and demethylation. The more toxic forms of arsenic are likely to be produces by methylation. Dimethylarsinous acid (DMA) is one of the most harmful arsenic metabolites produced by human cells. Monomethylarsonous is another of the most harmful arsenic metabolites produced in human cells ( Soza-Ried et al., 2019). b. (2 pt) Humans do not all have the same sensitivity to arsenic toxicity. Provide an explanation related to biotransformation. Tell me how the potential for arsenic toxicity would change (i.e., increases or decreases toxicity). As a result of genetic diversity and variations in biotransformation efficacy, all humans are not equally sensitive to the harmful effects of arsenic. In fact, people who have fewer effective biotransformation pathways may be more susceptible to arsenic poisoning. Additionally arsenic toxicity susceptibility may be influenced by genetic diversity (Faita et al., 2013 & Chi et al., 2018). c. (1 pt) How does the EPA classify the human carcinogenicity of arsenic? How is that classification defined? On what observations did they base this classification? According to the EPA, arsenic is recognized human carcinogen, putting it in Group A. This group is described as a carcinogen to humans as it is based on ample human evidence of carcinogenicity. They based this decision to classify arsenic as a carcinogen in this group as there was a significant amount of epidemiological and experimental evidence that proves a relationship between exposure to arsenic and cancer (Obinaju, 2021) (EPA, 2017).

4. (1 pt) Given that arsenic is a non-genotoxic carcinogen that causes hypomethylation of DNA, is arsenic’s effect more likely mediated through modification of oncogenes or tumor suppressors? Explain. Changes in gene methylation, mediated by arsenic, in the form of DNA hypomethylation, have suggested that they activate oncogene expression or silence tumor suppressors genes, which leads to long-term changes in the activity of genes in control of cell transformation ( Reichard et al., 2010) 2. (4 pts) In 2008, infants in China were being admitted for treatment of kidney stones at an unprecedented rate. It was discovered that infant formula was being intentionally tainted with melamine to artificially raise the apparent protein content. Rats were treated with melamine in their feed for 13 weeks and analyzed for bladder stone formation. The data are as follows (*Significant increase in stone formation)(NTP, 1983): 63 mg/kg/d * 126 mg/kg/d * 252 mg/kg/d * 502 mg/kg/d a. (2 pt) Which dose would you use as the point of departure in a reference dose calculation and what kind of POD is it? I would use the LOAEL as the point of departure in a reference dose calculation, the kind of POD this is the Benchmark Dose b. (1 pt ) Based on the POD you identified above, calculate a reference dose (show your work). Make sure to identify and justify the uncertainty factors you use. RfD = POD/UF 0.2mg/kg/day * 10X = 2 mg/kg/day A standard uncertainty factor of 10 is usually used (10X for inter-individual variability and 10X for extrapolation from animals to humans) c. (2 pt ) We can calculate a maximum daily melamine dose for a 6 month old child (based on the concentration of melamine in the formula, the average daily consumption

of formula and the average body weight) of 106 mg/kg/day. Based on your understanding of a reference dose, explain why this exposure level was of concern. The maximum daily melamine for a 6-month-old child is 106 mg/kg/day. This is problematic and poses a potential hazard as the exposure for melamine is much higher than the reference dose, over 50 times higher to be exact. The purpose of the reference understands the level of which a toxicant is relatively safe when consumed. With a daily maximum does much higher than the reference dose causes major concern as it could be at levels that cause adverse health effects. 1. (11 pts ) Download and read: Sorg, et al. 2009. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) poisoning in Victor Yushchenko: identification and measurement of TCDD metabolites. Lancet 374: 1179–85. https://www.sciencedirect.com/science/article/abs/pii/S0140673609609120 For useful information see: https://wwwn.cdc.gov/TSP/PHS/PHS.aspx?phsid=361&toxid=63#bookmark04 http://www.who.int/mediacentre/factsheets/fs225/en/ Based on the article, class notes and online resources, answer the following questions. a) (2 pt ) What is the major route of exposure and process of elimination of TCDD? Consider this as an exposure to the general public . The major route of exposure is through inhalation and ingestion, with inhalation being the most common route of exposure to the general population. Once absorbed, TCDD is processed in the liver, is metabolized and then excreted via feces or urine. b) (2 pt ) Was the elimination of TCDD in Viktor Yuchenko constant over time? Y/N? If not, how so? No, it was not constant over time. The plasma concentration of TCDD initially increased rapidly during the first 24 hours, then slowed down before plateauing. c) (2 pt ) Compare/contrast the distribution of TCDD and PFOA in adipose tissue and blood. Are they similar/different? Explain why/why not. The distribution of TCDD and POFA and adipose tissue and blood vary significantly. TCDD binds to proteins in the blood and is then stored in adipose tissue, where overtime, it is slowly released back into the blood. PFOA, is distributed between adipose tissue and blood with higher portions in blood than in adipose tissue. This is the case because PFOA is lipophilic, which is why it is stored in adipose tissue (Cranmer et al., 2000) d) (1.5 pt ) What was the half-life of TCDD in Viktor Yushchenko? The half-life of TCDD in Viktor Yushchenko was 15.4 months. e) (2 pt ) How did the half-life of TCDD in Yushchenko compare to the half-life predicted in humans with moderate exposure? Explain why they are different.

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The half-life of TCDD in humans with moderate exposure is 36-120 months, which is significantly longer than Viktor Yuschenko’s half-life of TCDD at 15.4 months. Yushchenko’s half-life was around twice to almost 8 times less than a human with moderate exposure half-life of TCDD would be. These numbers are different because there is an inverse association between half-life and tissue concentration. When individuals are exposed to high TCDD levels, and thus have high tissue concentration of TCDD, the half-life for TCDD is much smaller than it is for those who are moderately exposed to the chemical. In other words, because he experiences a much higher dose of the chemical, than what is seen in moderate exposures, there was a faster elimination rate because of the inverse association between the two factors. High concentrations of TCDD might be needed to activate these phase I enzymes, 8 , 15 , 32 and therefore might explain why the TCDD half-life depends on the degree of exposure to TCDD. Inverse association of the half-life with tissue concentration f) (1.5 pt ) Suppose that Yushchenko was poisoned slowly, on a daily basis, rather than in one large single exposure. The plasma concentration vs time graph would eventually plateau (i.e. stop increasing). Why? This would occur because the body would have time to process and eliminate the TCDD before the next dose was taken which would result in a steady concentration over time. Chi, L., Gao, B., Tu, P., Liu, W., Xue, J., Lai, Y., Ru, H., & Lu, K. (2018). Individual susceptibility to arsenic-induced diseases: The role of host genetics, nutritional status and the gut microbiome. Mammalian genome : Official journal of the International Mammalian Genome Society , 29 (1-2), 63. https://doi.org/10.1007/s00335-018-9736-9 Environmental Protection Agency. (2017, July 28). Arsenic, inorganic CASRN 7440-38-2 | DTXSID4023886 | iris | US EPA, Ord . EPA. https://cfpub.epa.gov/ncea/iris2/chemicallanding.cfm?substance_nmbr=278 Faita, F., Cori, L., Bianchi, F., & Andreassi, M. G. (2013). Arsenic-Induced Genotoxicity and Genetic Susceptibility to Arsenic-Related Pathologies. International Journal of Environmental Research and Public Health , 10 (4), 1527-1546. https://doi.org/10.3390/ijerph10041527 Morris Cranmer, Shirley Louie, Richard H. Kennedy, Philip A. Kern, Vivian A. Fonseca, Exposure to 2,3,7,8-Tetrachlorodibenzo- p -dioxin (TCDD) Is Associated with Hyperinsulinemia and Insulin Resistance, Toxicological Sciences , Volume 56, Issue 2, August 2000, Pages 431– 436, https://doi.org/10.1093/toxsci/56.2.431 Obinaju, B. E. (2021). Evaluation of arsenic toxicity and its role in carcinogenicity. International Journal of Public Health and Epidemiology, 10(1), 001-006. Reichard, J. F., & Puga, A. (2010). Effects of arsenic exposure on DNA methylation and epigenetic gene regulation. Epigenomics , 2 (1), 87. https://doi.org/10.2217/epi.09.45

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