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Response to Comment on “Chronic Disease and Early Exposure to Air-Borne Mixtures. 2. Exposure Assessment” Aylward et al. appear to misunderstand my remarks concerning the sex ratio and dioxin and why I refer to sex ratio. The sex ratio was, and remains for me, a marker of potential population exposure to the family of dioxin congenors, including TCDD. Even a cursory examination of the literature will reveal numerous examples where inverted sex ratios appear to follow chronic exposure to dioxins (1–5) or to stress (6). Dioxins per se are widely identified as stressors in mammals. The presence of chloride in fuel is a necessary and sufficient condition to ensure the formation of dioxins and furans downwind from the source (7–10) Dioxin congenors, as a byproduct of combustion, are reported in FIREv2.6 (11). For each census from 1921 to 1991 I obtained the total population of Canada, the total number of males and females and the total number of males and females in the first cohort, age 0-4. I calculated the sex ratio of the total population and the first cohort. I applied stochastic analysis to the data using 100,000 iterations, repeated with a Gamma distribution, using Crystal Ball and Excel. The distribution of the population sex ratio, pop SR, about the median, over the full range of time, is pop SR ) 0.5039 (C.I. 2.5-97.5th, 0.4788, 0.5296), with standard deviation ) 0.0129, skew ) 0.05, and kurtosis ) 3.04. The distribution of the sex ratio in the first cohort, first SR, about the median is first SR ) 0.5129 (C.I. 2.5-97.5th, 0.4872, 0.5392) with standard deviation ) 0.0132, skew ) 0.04, and kurtosis ) 3.03. The distributions of the two sex ratios, over time, are in Figure 1. The study conditions of Part 2 examine persons living within 25 km of any instance of kraft or sulfite pulp mills, coke ovens, oil refineries, copper, nickel, or lead/zinc smelters operating in Canada during the period 1967–1970. Exposure is assumed when a person inhabits the study area during the study period for at least 1 year. I calculated the sex ratio in each community containing these seven types of heavy industry in Canada, using the total population reported in the 1991 census. The resulting values of sex ratio were also analyzed for the underlying distribution with stochastic analysis. The median and fifth percentile for each source-type are in Table 1 and reported here for the first time. The minimum population potentially affected is on the bottom line of Table 1. With the possible exception of lead/zinc smelters, the fifth percentile C.I. sex ratios for each community with heavy industry (Table 1) are below the 2.5th percentile of the population cohort and the first cohort. This infers to me the environment of these communities is affected by external factors over and above the standard SES fluctuation expected, and as such, the principal industries in these communities can legitimately be examined for cause. The blank records in Figure 1 are to provide a more visible color profile. An animal is under chronic stress when the prevailing conditions mean the adreno-corticosteroid reaction to stress is activated for more than brief periods of time. If the mother perceives conditions as stressful, no matter what the nature of the stressor, the same adreno-corticosteroid reaction is activated at a low level over a period of time. Because of the physiological link between chronic stress and increased 2202
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FIGURE 1
TABLE 1. Sex Ratio by Source-Type source
kraft pulp
sulfite coke oil lead/ copper nickel pulp ovens refineries zinc
median 0.5066 0.4912 0.4866 0.4992 0.4933 0.4993 0.4816 lower 5th 0.4764 0.4684 0.4594 0.4758 0.4728 0.4587 0.4816 population 519,991 732,955 438,125 2,850,781 147,450 107,860 14,369
production of testosterone in females a stressed female will experience a rise in her normal level of testosterone, and conceive males instead of females. Timing of the stressor is extremely important (12). The cause of male bias and the reason why, under stress, fewer males are born, is addressed with the “damaged cohort” hypothesis and the “culled cohort” hypothesis. When the pregnant mother experiences stress the deleterious effects will be most pronounced in the “frailest” male, subsequently “culled”. If the frailest male is culled early, the remaining males will be healthier (13). I remind that dioxins are widely known to cause oxidative stress within organisms. Dioxins are found in human follicular fluid at concentrations of approximately 1 pg/mL (0.01 TEQ/mL) (14, 15). However, my paper is not about the sex ratio per se. Part 2 is about retrospective exposure assessment to industrial emissions. Aylward et al. refer to an examination of dioxin exposure (their ref 3) and report that dioxin levels in food, environmental media, and human tissues have steadily declined since the late 1960s. Estimating dioxin exposure at a time when dioxin was hardly known or understood is difficult. My solution was to use sex ratio as a surrogate for dioxin exposure, since later, well-designed studies associated the two. I adopted the approximate solution of Jones et al. (RASH ) Rapid Assessment of Screening Hazard) to solve this problem because it is a simple to use, elegant solution that provides highly accurate estimates to extremely difficult chemical-mixture problems. Aylward et al. are correct in criticizing my use of the word “exact”, when it should have been referring to the mixture of chemicals in the plume that have an associated relative potency. We both use approximations. Subjects living in the study area probably move away before their cancer manifests but their original exposure to the chemical mixture from industry’s releases, including dioxins, are documented in EQDB. Dr Valerie Grant, Auckland, NZ, assisted me to understand the biology of the sex ratio after Part 2 appeared and provided 10.1021/es703079w CCC: $40.75
2008 American Chemical Society
Published on Web 02/19/2008
references, comment, and context. For her assistance I am profoundly grateful.
Literature Cited (1) Jongbloet, P. H.; Roeleveld, N.; Groenwoud, H. M. Where the boys aren’t: dioxin and the sex ratio. Environ. Health Perspect. 2002, 110 (1), 1–3. (2) Ikeda, M.; Tamura, M.; Yamashita, J.; Suzuki, C.; Tomita, T. Repeated in utero and lactational 2,3,7,8-tetrachlorodibenzop-dioxin exposure affects male gonads in offspring leading to sex ratio changes in F2 progeny. Toxicol. Appl. Pharmacol. 2005, 206, 351–355. (3) Ryan, J. J.; Amirova, Z.; Carrier, G. Sex ratios of Russian pesticide producers exposed to dioxin. Environ. Health Perspect. 2002, 110 (11), 699–701. (4) Pesatori, A. C.; Consonni, D.; Bachetti, S.; Zochetti, C.; Bonzini, M.; Baccarelli, A.; Bertazzi, P. A. Short- and long-term morbidity and mortality in the population exposed to dioxin after the ”Seveso” incident. Ind. Health 2003, 413, 127–138. (5) Mocarelli, P.; Gerthoux, P. M.; Ferrari, E.; Patterson, D. G., Jr.; Kieszak, S. M.; Brambilla, P.; Vincoli, N.; Signorini, S.; Tranacere, P.; Carreri, V.; Sampson, E. J.; Turner, W. E.; Needham, L. L. Paternal concentration of dioxin and sex ratio of offspring. Lancet 2000, 355 (9218), 1858–1863. (6) Kemkes, A. Secondary sex ratio variation during stressful time: the impact of the French revolutionary wars on a German parish (1787–1802). Am. J. Hum. Biol. 2006, 18 (6), 806–821. (7) Yasuhara, A.; Katami, T.; Okuda, T.; Ohno, N.; Shibamoto, T. Formation Of Dioxins During The Combustion Of Newspapers In The Presence Of Sodium Chloride And Poly(Vinyl Chloride). Environ. Sci. Technol. 2001, 357, 1373–1378. (8) Fleischer, O.; Wichmann, H.; Lorenz, W. Release of polychlorinated dibenzo-p-dioxins and dibenzofurans by setting off fireworks. Chemosphere 1999, 39 (6), 925–932.
(9) Mihaltz, P.; Pal, F.; Siska, J.; Duchateau, F. The Evaluation of Dioxin Emissions From Pilot Scale Incineration of Organochlorine Compounds. Cent. Eur. J. Public Health 2000, 8, 12–3. (10) Pandompatam, B.; Kumar, Y.; Guo, I.; Liem, A. J. Comparison Of PCDD And PCDF Emissions From Hog Fuel Boilers And Hospital Waste Incinerators. Chemosphere 1997, 34 (5–7), 1065–1073. (11) U.S. EPA. Factor Information and Retrieval, FIRE v 2.6; U.S. EPA: Washington, DC, 1998. (12) Grant, V. J. Could maternal testosterone levels govern mammalian sex ratio deviations? J. Theor. Biol. 2007, 246, 708–719. (13) Catalano, R.; Bruckner, T. Male lifespan and secondary sex ratio. Am. J. Human Biol. 2006, 18, 783–790. (14) Tsutsumi, O.; Uechi, H.; Sone, H.; Yonemoto, J.; Takai, Y.; Momoeda, M.; Tohyama, C.; Hashimoto, S.; Morita, M.; Taketani, Y. Presence of dioxins in human follicular fluid: their possible stage-specific action on the development of pre-implantation mouse embryos. Biochem. Biophys. Res. Commun. 1998, 250 (2), 498–501. (15) Tsutsumi, O. Assessment of human contamination of estrogenic endocrine-disrupting chemicals and their risk for human reproduction. J. Steroid Biochem. Mol. Biol. 2005, 93 (2–5), 325–330.
James Argo IntrAmericas Center for Environment and Health, Box 101, Wolfe Island, ON, K0H2Y0, Canada ES703079W
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