Association of Dioxin and Dioxin-Like Congeners with Hypertension Surbhi Trivedi; and Rohit R

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Association of Dioxin and Dioxin-like Congeners With Hypertension Surbhi Trivedi; and Rohit R. Arora, MD Although 7 of 8 studies found moderate evidence of an association with hypertension in patients with at least 1 chemical congener, these studies cannot prove a causal relationship.

Ms. Trivedi is a Medical ersistent organic pollutants (POPs), mals and persist in the food chain.3,5,6 These Student, and Dr. Arora is a Professor at Rosalind endocrine-disrupting, lipophilic chemicals of interest (COIs) are graded for Franklin University of Pchemicals that concentrate in adi- toxicity based on toxic equivalency factors Medicine and Science in pose tissue, increasingly are being studied relative to TCDDs in a 2005 World Health Chicago, Illinois. Dr. Arora for a wide range of health effects.1 Persis- Organization assessment.3 is Chief of Cardiology and Chair of the Department of tent organic pollutants include bisphenol Polychlorinated dibenzofurans (PCDFs), Medicine at Captain James A, phthalates, dioxins, hexachlorobenzene, TCDD, PCBs, PCDDs, and other environ- A. Lovell Federal Health dichlorodiphenyltrichloroethane (DDT), mental toxins are being studied as possible Care Center in Chicago. Correspondence: polybrominated diphenyl ethers, and poly- contributing factors in the development of Ms. Trivedi (surbhi.trivedi@ chlorinated biphenyls (PCBs). Chlorinated hypertension. The authors review the results gmail.com). dibenzo-p-dioxins are known as polychlo- of several recent studies on COI exposure rinated dibenzodioxins (PCDDs), or sim- and hypertension. ply dioxins. Categorization of this group of In 2017, the American College of Cardiol- chemicals is based on the structural chlori- ogy and the American Heart Association low- nated constituents. Of the 75 congener mol- ered the threshold for hypertension to systolic ecules, 2,3,7,8-tetrachlorodibenzo-p-dioxin blood pressure (SBP) > 130 mm Hg and di- (TCDD) is the most toxic, and this dioxin, astolic blood pressure (DBP) > 80 mm Hg.7 given its more serious health implications, This new guideline would categorize 46% of has been studied the most.1,2 the US population as having hypertension, Because it was a contaminant in the her- compared with 32% under the former cutoff bicide Agent Orange, the main defoliant of 140/90 mm Hg.7 Modifiable factors (eg, used by the US military in southern Viet- diet, body mass index [BMI], smoking, al- nam during the Vietnam War, TCDD is of cohol, physical activity) and nonmodifi- primary interest. Agent Orange consists of able factors (eg, age, family history, sex, 2,4-dichlorophenoxyacetic acid (2,4-D) and race/ethnicity) have a role in the patho- 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) physiology of hypertension. Between 90% in equal parts. Like other dioxins, TCDD is and 95% of hypertension is considered pri- lipophilic and retained in adipose tissue.1,3 mary. Hypertension increases the risk of Contemporaneous sources include occupa- developing ischemic heart disease, athero- tional and residential exposure from pulp sclerosis, aortic dissection, small blood ves- and paper mills, metallurgy, incinerators, in- sel disease, congestive heart failure, and dustrial waste, fossil fuel combustion, and in- renal failure, and thus results in consider- dustrial accidents and poisonings.1-4 able morbidity and mortality each year.8 Another main class of POPs, polychlorinated benzenes, includes 209 synthetic PCB CONTAMINANT EXPOSURE AND congener chemicals, a subset of which is re- HYPERTENSION RISK ferred to as dioxin-like PCBs.1 Organochlorine Vietnam-Era Army Chemical Corps (OC) pesticides and PCBs were once manu- The US Army Chemical Corps (ACC) Viet- factured as lubricants and coolants for elec- nam-Era Veterans Health Study (2012-2013) tronics but are now banned; nevertheless, recorded the long-term health burdens they remain concentrated in fish and mam- imposed by Agent Orange exposure and

20 • FEDERAL PRACTITIONER • MAY 2018 mdedge.com/fedprac Vietnam War service.9,10 This cross-sectional study reexamined a subset of 5,609 Vietnam- era ACC veterans for an association of self- reported, physician-diagnosed hypertension (≥ 140/90 mm Hg) and herbicide spraying history confirmed with serum TCDD levels. The 22 Army units that made up the ACC were in charge of spreading Agent Orange and other defoliants on opposition camps between 1965 and 1973. The herbicide was dis- persed aerially and on the ground. The ACC was also responsible for dispensing napalm, tear gas, and other chemicals. A previous phone survey found an association of self-reported hypertension and herbicide spraying in ACC veterans with associated Vietnam service and herbicide spraying history, verified with serum TCDD levels (odds ratio [OR], 1.26; 95% confidence inter- val [CI], 1.00-1.58).9 Median age of ACC veterans with Vietnam War service at the time of the survey was 53 years. The 2012-2013 study assessed respondents with a record of their serum TCDD COIs). The Korean veterans were classified measurements from the time of the survey.10 by military assignment and by their prox- Most of the respondents were aged in their imity to areas sprayed with Agent Orange, 60s. The stated purpose of the health study according to the military records of 3 US was to examine the association of Vietnam combat units: Capital Division, 9th Division, veterans’ occupational herbicide exposure and Marine Second Brigade. The ROK vet- and hypertension risk, rather than isolate a erans in those units presumably would have certain responsible chemical, though serum similar levels of Agent Orange exposure. TCDD levels were used to confirm spraying The questionnaire response rate was 69%. history. After adjustments for age, tobacco The 114,562 respondents were divided into use, alcohol use, race, and BMI but not salt groups based on self-perceived exposure (no, intake, family history of hypertension, psy- low, moderate, high) and qualitative expo- chiatric health, or diabetes mellitus (DM) sure level, derived from service history (bat- comorbidity, the OR of self-reported, physi- talion/company, division/brigade). After cian-diagnosed hypertension was 1.74 (95% adjusting for BMI, smoking, alcohol use, CI, 1.44-2.11) for sprayers and 1.26 (95% CI, physical activity, use of nonoccupational 1.05-1.53) for Vietnam veterans.10 herbicides, education, income, and military rank, Yi and colleagues found a statistically Vietnam War Veterans From Korea significant association of hypertension and Soldiers of the Republic of Korea (ROK) self-reported perceived Agent Orange expo- who fought in the Vietnam War also were sure (P < .001) and a statistically significant exposed to Agent Orange and other defo- association of hypertension and exposure in liants and herbicides. In 2013, Yi and col- the division/brigade group with the highest ex- leagues contacted 187,897 ROK Vietnam posure level (P < .001).11 The highest ORs were veterans to analyze their Agent Orange ex- found for high- vs low-exposure and moder- posure and self-reported diseases decades ate- vs low-exposure subsets in self-reported after the war.11 By mail, the researchers ad- perceived Agent Orange levels: 1.60 (95% CI, ministered a questionnaire of perceived 1.56-1.65) and 1.70 (95% CI, 1.64-1.77), re- Agent Orange exposure (eg, spraying, han- spectively. However, adjusted ORs in proxim- dling spray equipment, having contact with ity-based exposure for all groups were > 1.03.

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Table Studies of Dioxins and Hypertension

Data Collection Chemical Exposure Authors, y Study Type Period (No.) Subjects Category Study Results

Cypel and Cross-sectional January— Vietnam-era Army Serum TCDD value Significant association colleagues, December Chemical Corps between exposure and 201610 2013 (3,086) veterans hypertension

Cappelletti and Retrospective 1979—2009 Trentino, Occupational PCB Uncomplicated colleagues, cohort (331) Italy steelworkers exposure in electric hypertension; 201613 arc furnaces complicated hypertension

Lind and Cross-sectional Started in Uppsala, Sweden Serum persistent After adjusting for multiple colleagues, 2001 (1,016) population aged organic pollutants variables, no significant 201414 ≥ 70 years association except with 1 chemical congener

Yi and Cross-sectional July 2004 Republic of Recorded military Perceived moderate colleagues, (114,562) Korea veterans spraying duties and vs low exposure; 201411 of Vietnam War perceived exposure perceived high vs low to Agent Orange exposure

Valera and Geographic September— Inuits of Nunavik, Serum PCB Significant association colleagues, area December Canada congeners between some congeners 20135 1992 (315) and hypertension

Valera and Geographic 2005—2011 Inuits of Greenland Serum PCB No significant association colleagues, area (1,614) between most PCBs and 20136 hypertension

Nakamoto and Cross- 2002—2008 Japanese Background Significant association colleagues, sectional, (2,266) populations nonoccupational between serum toxic 201312 geographic chemical of interest equivalents and area, exposure in urban areas and hypertension farming and fishing villages

Ha and Population- 1999—2002 NHANES Serum persistent PCBs and hypertension colleagues, based cross- (524) organic pollutant associated in men but not 200915 sectional levels in women

Abbreviations: NHANES, National Health and Nutrition Examination Survey; PCB, polychlorinated biphenyl; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Inuits in Canada and Greenland blood drawn. Laboratories measured serum To study total PCBs, non-dioxin-like PCBs, PCB congeners and 13 chlorinated pesti- OC pesticides, and their metabolites in cides or their metabolites. Blood pressure plasma, public health researchers Valera (BP) was measured 3 times, and the last and colleagues focused on the Inuit town of 2 measurements averaged. Hypertension Nunavik (in Canada), where there is con- was defined as SBP ≥ 140 mm Hg and/or tamination from foods like fish, a mainstay DBP ≥ 90 mm Hg. of the Inuit diet.5 A health survey was sent Of the 518 participants, 315 (134 men, to 400 households randomly selected from 181 women) had complete BP, serum POP 1,378 households in 14 villages. Data were levels, and confounding variables recorded, collected between September and Decem- and these were subsequently analyzed. ber 1992. In total, 518 people between ages Mean age was 32.7 years. Polychlorinated 18 and 74 years agreed to undergo a phys- biphenyls congeners 105 and 118 were ical examination, and 492 agreed to have higher in women than in men; no other

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congeners were quantitatively different. As- the women. Participants volunteered their sociations between POP levels and hyper- disease histories, which included physician- tension were analyzed with multiple logistic diagnosed hypertension (SBP ≥ 140 mm Hg regression modeling, with adjustments for or DBP ≥ 90 mm Hg). Logistic regression age, sex, fasting blood glucose, waist circum- analyses were adjusted for BMI, sex, age, ference, smoking, alcohol use, and physical regional residential area, smoking, alco- activity, as well as the common contaminants hol use, and survey year. In fishing regions, lead, mercury, and omega-3 polyunsatu- PCDDs, PCDFs, and DL-PCBs were signifi- rated fatty acids (n-3 PUFA).The research- cantly higher than in the other regions. Of ers adjusted for n-3 PUFA because of the the 2,266 participants, 647 reported physi- posited BP-lowering effects. Inuits consume cian-diagnosed hypertension. Dividing the large amounts of the polyunsaturated fatty toxic equivalents of serum COI levels into acids DHA (docosahexaenoic acid) and quartiles of concentration, Nakamoto and EPA (eicosapentaenoic acid).5 colleagues found a statistically significant Using congeners found in at least association of hypertension and increased 70% of the total samples, the study au- toxic equivalent levels of PCDDs, PCDFs, thors found a statistically significant as- DL-PCBs, and total dioxins. sociation between certain PCBs, both dioxin-like (DL-PCBs) and non-dioxin- Italian Male Steelworkers like (NDL-PCBs), and increased risk of hy- In a 2016 retrospective cohort study, Cap- pertension. Congeners 101, 105 (DL-PCB), pelletti and colleagues assessed the health 138, and 187, as well as p,p'-DDE, were also burden of workers at a steel recycling significantly associated with a higher risk of plant in Trento, Italy. The plant, which had hypertension. Congener 99 was associated been using an electric arc furnace without with increased SBP, and congener 118 (DL- a coke oven, had been exposing workers PCB) was associated with increased SBP and to dust containing PCBs, PCDDs, PCDFs, DBP. Some congeners, such as the OC pesti- and other metals.13 Each hour, roughly cides, p,p'-DDT, β-hexachlorocyclohexane, 2 to 5 kg of dust was being released in- and oxychlordane, were inversely associated side the plant (diffuse emissions), and ex- with hypertension. posure extended to a 2-km radius around In 2012, Valera and colleagues conducted the plant. A cohort of 331 plant workers, a similar study of Greenland Inuits who also identified and assessed through company consume marine mammals and fish and pres- records, had been exposed to diffuse emis- ent with high POP levels.6 Despite correcting sions for at least 1 year between 1979 and for n-3 PUFA, they found no significant as- 2009. This group was compared with a sociation involving DL-PCBs, NDL-PCBs, or control group of 32 office workers from OC pesticides. that company, as identified by company records. The authors found a risk ratio (RR) Japanese Background Exposures of 2.23 in cases of noncomplicated hy- Nakamoto and colleagues conducted a pertension and an RR of 2.01 in cases of cross-sectional study of 2,266 Japanese complicated hypertension, defined as hy- women and men who had been exposed pertension with organ damage. to background (vs occupational or war- time) levels of dioxins, including PCDDs, Elderly in Sweden PCDFs, and DL-PCBs.12 The dioxins likely In a study of 1,016 Swedish men and originated from combustion of chlorinated women who were aged 70 years or older materials and older manufactured electron- and were living in Uppsala, Sweden, Lind ics components. The study participants had and colleagues calculated average su- lived in urban areas or in farming or fishing pine BP from 3 sphygmomanometer mea- villages for at least 10 consecutive years and surements after 30 minutes of rest.14 The had no concomitant occupational exposure researchers used high-resolution gas chro- to dioxins. Mean (SD) age was 43.5 (13.6) matography/high-resolution mass spec- years for the men and 45.3 (14.0) years for trometry (HRGC/HRMS) to measure the

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serum levels of a set of 23 POPs—16 PCB and colleagues postulated that this ap- congeners, 5 OC pesticides, 1 brominated proach of studying a US population subset biphenyl ether congener, and octachloro- of patients with background exposure to p-dibenzodioxin—and lipid-normalized POPs, instead of groups with high concen- the values. They used logistic regression trations of exposure (eg, Vietnam War vet- to assess POP levels and prevalent hyper- erans or those exposed occupationally or tension (BP ≥ 140/90 mm Hg or use of an- in industrial accidents), provides an alter- tihypertensives), adjusting for sex, BMI, native observable effect of long-term, low- smoking status, exercise, and education. dose exposure of a blend of POPs.15 Among the COIs with the highest circulat- ing lipid-normalized POP levels were PCB DISCUSSION congeners 180, 138, and 170 and DDE. In vivo and in vitro studies have found that There was no clear relationship between dioxins induce a subset of 35 genes, in- toxic equivalents and hypertension; after cluding microsomal P450 enzymes, ki- multivariate adjustments, only DDE showed nases and phosphates, and DNA repair a statistically significant OR: 1.25 (95% CI, proteins. A microarray profile of cardio- 1.07-1.47). vascular murine tissue and cultured vascular smooth muscle cells exposed to Organic Pollutants and Hypertension TCDD found known dioxin-inducible Using National Health and Nutrition Exam- genes Cyp1b1, a phase 1 drug metabolism ination Survey (NHANES) data from 1999 enzyme, and Aldh3A1, another drug me- to 2002, Ha and colleagues conducted a tabolism gene up-regulated, among lec- cross-sectional study of a 524-adult subset tin-related natural killer cell receptor, of patients who were exposed to background insulin-like growth factor binding protein, levels of POPs and had newly diagnosed and cyclin G2.16 hypertension (≥ 140/90 mm Hg).15 In the Dioxins bind avidly to the aryl hydro- NHANES study, the CDC collected stan- carbon receptor (AhR), a cytosolic tran- dardized patient history information, physi- scription factor that also interacts with cal examination findings, and venous blood other xenobiotic compounds with varying sample results. Recorded BP data points were affinities. TCDD is one of the most potent the averages of 3 separate SBP and DBP read- ligands for AhR, and other DL compounds ings from a sphygmomanometer, as recom- have a lower binding affinity. AhR dimer- mended by the AHA. The NHANES study izes in the nucleus with the AhR nuclear recorded POPs with HRGC/HRMS. translocator and then binds genomic di- Ha and colleagues selected 12 POPs, oxin response elements and induces the and standardized the COI concentrations expression of cytochrome P450 genes, against lipid concentration. The lipid-stan- such as CYP1A1.17 dardized POP concentrations used were The AhRs are highly expressed in the at a higher level of detection and found in vascular endothelium.17 Agbor and col- at least 60% of the study patients. The re- leagues found that mice with endothelial searchers used a logistic regression model AhR knockouts showed decreased baseline to calculate multivariate-adjusted OR sep- SBP and DBP.18 When challenged with an- arately in men and women, adjusting for giotensin II, a potent vasoconstrictor, AhR- race/ethnicity, smoking/alcohol use, physi- /- mice failed to show an increase in DBP. cal activity, BMI, cotinine level, and income AhR-/- exhibited reduced ex vivo aortic con- level. Among the 56 men and 67 women traction in the presence of angiotensin II with newly diagnosed prevalent hyperten- in aortas with perivascular adipose tissue. sion, PCDD levels in women were posi- Notably, compared with wild-type mice, tively associated with hypertension but AhR-/- mice had reduced renin-angiotensin not correlated with higher or lower toxic system gene expression in the visceral adi- equivalency factors. Dioxin and NDL-PCBs pose, linking the AhR receptor with the en- were positively associated with hyperten- dogenous renin-angiotensin-aldosterone sion in men but negatively in women. Ha system (RAAS).

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Early studies have shown that mice lack- the 8 studies reviewed in this study found ing AhR do not demonstrate TCDD toxicity.20 moderate evidence of association in patients More recently, Kopf and colleagues found that with at least 1 chemical congener and a cer- TCDD exposure in mice led to increased BP tain subset of the study population (Table). and cardiac hypertrophy, possibly linked to Given their nature, however, these studies increased superoxide production in the vas- cannot prove a causal relationship, and their culature.21 When exposed to TCDD, mice results are only suggestive and should be showed enhanced CYP1A1 mRNA expres- treated as such. sion in the left ventricle, kidney, and aorta by The Vietnam-Era Veterans Health Study day 35 and increased CYP1B1 mRNA expres- found a higher OR of developing hypertension in the left ventricle after 60 days. Within sion in herbicide sprayers than in its control the first week of TCDD exposure, the mean group. Korean Vietnam War veterans strati- arterial pressure for the exposure group was fied by either self-reported risk or military as- statistically significantly increased, showing a signment also had significant associations. trend of peaks and plateaus. Mice exposed to For male steelworkers in Italy, occupational TCDD also showed left ventricular concen- exposure had a moderately higher RR in the tric hypertrophy, which is typical of systemic exposure cohort. In the NHANES study, back- hypertension.8,21 Kerley-Hamilton and col- ground levels of POPs were positively asso- leagues found that AhR ligand activation in- ciated, but only in men. A nonoccupational creased atherosclerosis.22 study in urban and rural areas of Japan found Most hypertension is idiopathic. Research a significant association between dioxins and into the downstream effects of AhR suggests hypertension. A nonoccupational study of el- it induces vascular oxidative stress and in- derly Swedes found a significant association creases atherosclerosis.22 It is unclear whether with only 1 chemical congener. A study of In- this is an initiating or synergistic factor in the uits in Greenland found no significant asso- development of hypertension. The study re- ciations, but a study of Inuits in Canada did sults described here indicate that dioxins ini- yield an association. tiate BP changes through the endothelial AhR Recent studies maintain the 2012 veterans receptor, but this mechanism has been proved update regarding a limited but suggestive as- only in an animal model. Ongoing studies are sociation of dioxin and hypertension.4 Despite needed to examine the molecular changes in having high power because of the number of humans. Clinicians can be advised that dioxin exposed patients, these observational stud- exposure, rather than being an initiating fac- ies can posit only an associative relationship, tor, would at most contribute to an accumu- not a causal one. These studies also are lim- lating series of assaults, including genetics, ited by their categorization of dioxin exposure lifestyle, and environmental factors, and that levels—ranging from perceived exposure to these assaults progress to hypertension only proximity and direct serum dioxin measure- after passing a threshold.23 Moreover, many ment. Moreover, chemical levels are measured of the studies described here categorized hy- an inconsistent number of years after expo- pertension under the guideline of 140/90 mm sure, and therefore, as dioxins are primarily Hg. Future studies may use the newer guide- metabolized by CYP genes, different meta- line, which will affect their results. bolic rates could account for different suscep- tibility to health effects.2 CONCLUSION In vivo animal studies could better char- Studies have shown an association between acterize the effect of time point of exposure dioxins and endocrine disruption, reproduc- and effects on hypertension. Studies could tive and developmental problems, and cer- also examine the synergistic effects of di- tain cancers.3,24 The Seveso Women’s Health oxins and other toxins, or smoking or al- Study of an industrial accident in Italy linked cohol use, on hypertension. New clinical dioxins to an incidence of DM, obesity, or guidelines for hypertension will have an metabolic syndrome.25 By contrast, evidence impact on studies. Overall, clinicians who of a link between dioxins and hypertension treat patients with known exposure to diox- has been limited and inconsistent. Seven of ins can suggest with moderate confidence

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that it is likely not a primary reason for the of Army Chemical Corps Vietnam veterans who sprayed defoliant in Vietnam. Am J Ind Med. 2006;49(11):875-884. development of hypertension. At most, di- 10. Cypel YS, Kress AM, Eber SM, Schneiderman AI, Davey oxin exposure is a contributing factor in the VJ. Herbicide exposure, Vietnam service, and hypertension risk in Army Chemical Corps veterans. J Occup Environ development of hypertension, with lifestyle, Med. 2016;58(11):1127-1136. smoking, diet, and genetics playing more 11. Yi SW, Ohrr H, Hong JS, Yi JJ. Agent Orange expo- compelling roles. sure and prevalence of self-reported diseases in Ko- rean Vietnam veterans. J Prev Med Public Health. 2013;46(5):213-225. Author disclosures 12. Nakamoto M, Arisawa K, Uemura H, et al. Associa- The authors report no actual or potential conflicts of interest tion between blood levels of PCDDs/PCDFs/dioxin-like with regard to this article. PCBs and history of allergic and other diseases in the Japanese population. Int Arch Occup Environ Health. Disclaimer 2013;86(8):849-859. The opinions expressed herein are those of the authors and do 13. Cappelletti R, Ceppi M, Claudatus J, Gennaro V. Health not necessarily reflect those of Federal Practitioner, Frontline status of male steel workers at an electric arc furnace Medical Communications Inc., the US Government, or any (EAF) in Trentino, Italy. J Occup Med Toxicol. 2016;11:7. of its agencies. This article may discuss unlabeled or inves- 14. Lind PM, Penell J, Salihovic S, van Bavel B, Lind L. Circu- tigational use of certain drugs. Please review the complete lating levels of p,p’-DDE are related to prevalent hyperten- prescribing information for specific drugs or drug combina- sion in the elderly. Environ Res. 2014;129:27-31. tions—including indications, contraindications, warnings, and 15. Ha MH, Lee DH, Son HK, Park SK, Jacobs DR Jr. As- adverse effects—before administering pharmacologic therapy sociation between serum concentrations of persistent to patients. organic pollutants and prevalence of newly diagnosed hypertension: results from the National Health and Nutri- References tion Examination Survey 1999–2002. J Hum Hypertens. 1. Van den Berg M, Birnbaum L, Bosveld AT, et al. Toxic 2009;23(4):274-286. equivalency factors (TEFs) for PCBs, PCDDs, PCDFs 16. Puga A, Sartor MA, Huang M, et al. Gene expression pro- for humans and wildlife. Environ Health Perspect. files of mouse aorta and cultured vascular smooth muscle 1998;106(12):775-792. cells differ widely, yet show common responses to dioxin 2. US Department of Health and Human Services, Pub- exposure. Cardiovasc Toxicol. 2004;4(4):385-404. lic Health Service, Agency for Toxic Substances and 17. Swanson HI, Bradfield CA. The AH-receptor: genet- Disease Registry, Koplan JP. Toxicological profile for ics, structure and function. Pharmacogenetics. chlorinated dibenzo-p-dioxins. https://www.atsdr.cdc 1993;3(5):213-230. .gov/toxprofiles/tp104.pdf. Published December 1998. 18. Agbor LN, Elased KM, Walker MK. Endothelial cell-specific Accessed April 3, 2018. aryl hydrocarbon receptor knockout mice exhibit hypoten- 3. Van den Berg M, Birnbaum LS, Denison M, et al. The sion mediated, in part, by an attenuated angiotensin II 2005 World Health Organization reevaluation of human responsiveness. Biochem Pharmacol. 2011;82(5):514-523. and mammalian toxic equivalency factors for dioxins and 19. Fujii-Kuriyama Y, Mimura J. Molecular mechanisms of AhR dioxin-like compounds. Toxicol Sci. 2006;93(2):223-241. functions in the regulation of cytochrome P450 genes. Bio- 4. Committee to Review the Health Effects in Vietnam Vet- chem Biophys Res Commun. 2005;338(1):311-317. erans of Exposure to Herbicides (Ninth Biennial Update); 20. 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