Replies

All right. Here are three abstracts. If you don't want to read it and try to understand it that's your problem.

I've provided you with a scientific study, you've provided me with anecdotal evidence and, so you say, a MDs OPINION. If you have nothing else I would consider this argument to be closed.

Exposure to Polychlorinated Dioxins and Furans (PCDD/F) and Mortality in Cohort of Workers From an Herbicide-Producing Plant in Hamburg, Federal Republic of Germany

American Journal of Epidemiology 1995; 142:1165-75

Dieter Flesch-Janys, Jurgen Berger, Petra Gurn, Alfred Manz, Sibylle Nagel, Hiltraud Waltsgott, and James H. Dwyer

Abstract

The relation between mortality (all cause: cancer, cardiovascular diseases, ischemic heart diseases, and exposure to polychlorinated dibenzo-p-dioxins and -furans (PCDD/F) was investigated in a retrospective cohort study. The cohort consisted of 1189 male workers in a chemical plant in Hamburg, Federal
Republic of Germany, who had produced phenoxy herbicides, chlorophenols, and other herbicides and insecticides known to be contaminated with 2,3,7,8 - tetrachlorodibenzo-p-dioxin and other, higher chlorinated dioxins and and furans. The authors reported previously on cancer mortality in this cohort for
the follow-up period 1952-1989. The current study covers the years 1092-1992 and investigated the relation of PCDD/F exposure to mortality using a quantitative estimate of PCDD/F exposure for the whole cohort derived from blood and adipose tissue in the estimation of relative risks (RRs) using year of
birth stratified Cox regression. An unexposed cohort of highest relative risk was observed for the highest 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) decile (RR=2.43, 95% confidence interval (CI) 1.80-3.29). Cancer mortality and mortality due to ischemic heart diseases showed a dose-dependent
relation with TCDD and all PCDD/F combined. The highest relative risks for cancer (RR=3.30, 95% CI 2.05-5.31) and ischemic heart diseases (RR=2.48, 95% CI 1.32 to 4.66) were observed in the highest PCDD/F exposure group. The pattern of effects and tests for trend were similar when the
lowest exposure group within the chemical worker cohort served as the reference, but the relative risks were smaller and the confidence intervals were larger. Potential confounding exposures complicate the interpretation of the internal comparison. These findings indicate a strong dose-dependent relation
between mortality due to cancer or ischemic heart diseases and exposure to polychlorinated dioxins and furans.

Estimation of the Cumulated Exposure to Polychlorinated Dibenzo-p-dioxins/furans and Standardized Mortality Ratio Analysis of Cancer Mortality by Dose in an Occupationally
Exposed Cohort

Dieter Flesch-Janys,1 Karen Steindorf,2 Petra Gurn,3 and Heiko Becher2

1Center for Chemical Workers' Health and Hamburg State Department of Work, Health, and Social Affairs, Hamburg, Germany; 2German Cancer Research Center, Heidelberg, Germany; 3Institute for Statistics, University of Bremen, Bremen, Germany

Abstract

For a cohort of 1189 male German former herbicide and insecticide workers with exposure to polychlorinated dibenzo-p-dioxins and -furans (PCDD/F), we
report an extended standardized mortality ratio (SMR) analysis based on a new quantitative exposure index. This index characterizes the cumulative lifetime
exposure by integrating the estimated concentration of PCDD/F at every point in time (area under the curve). Production department-specific dose rates were derived from blood levels and working histories of 275 workers by applying a first-order kinetic model. These dose rates were used to estimate exposure levels for all cohort members. Total mortality was elevated in the cohort; 413 deaths yielded an SMR of 1.15 (95% confidence interval [CI] 1.05, 1.27) compared to the mortality of the population of Germany. Overall cancer mortality (n=124) was significantly increased (SMR=1.41, 95% CI 1.17, 1.68). Various cancer sites showed significantly increased SMRs. The exposure index was used for an SMR analysis of total cancer mortality by dose. For 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) a significant trend (p=0.01) for the SMRs with increasing cumulative PCDD/F exposure was observed. The SMR in the first exposure quartile (0-125.2 ng/kgyears) was 1.24 (95% CI 0.82, 1.79), increasing to 1.73 (95% CI 1.21, 2.40) in the last quartile (2503.0 ng/kgyears). For all congeners combined as toxic equivalencies (TEQ) using international toxic equivalency factors, a significant increase in cancer mortality was in the second quartile (360.9-1614.4 ng/kgyears, SMR 1.64; 95% CI 1.13, 2.29) and the fourth quartile (5217.7 ng/kgyears TEQ, SMR 1.64, 95% CI 1.13, 2.29). The trend test was not significant. The results justify the use of this cohort for a quantitative risk assessment for TCDD and to a lesser extent for TEQ. -- Environ Health Perspect 106(Suppl 2):655-662 (1998). http://ehpnet1.niehs.nih.gov/docs/1998/Suppl-2/655-662flesch-janys/abstract.html

Key words: polychlorinated dibenzo-p-dioxins/furans, PCDD/F, occupational exposure, exposure quantification, area under the curve, cancer mortality, dose response, risk assessment

This paper is based on a presentation at the International Symposium on Dioxins and Furans: Epidemiologic Assessment of Cancer Risks and Other Human Health Effects held 7-8 November 1996 in Heidelberg, Germany. Manuscript received at EHP 28 May 1997; accepted 12 September 1997.

This study was supported by German Federal Environmental Agency grant 116 06 111.

Address correspondence to Dr. D. Flesch-Janys, Hamburg State Department of Work, Health, and Social Affairs, Health Office, Division Health and Environment, Tesdorpfstr. 8, D-20148 Hamburg, Germany. Telephone: 49 40 44195 630. Fax: 49 40 44195 624. E-mail: flesch@uke.uni-hamburg.de

Abbreviations used: CI, confidence interval; ß-HCH, beta-hexachlorocyclohexane; I-TEQ, international toxic equivalencies; PCDD/F, polychlorinated -p-dioxins/furans; SMR, standardized mortality ratio; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; TEQ, toxic equivalencies.

The following conclusions were ratified at the May 1998 COC meeting.

Introduction

i) The COC considered the available epidemiological and experimental data on 2,3,7,8-tetrachlorodibenzo[b,e][1,4]dioxin (2,3,7,8-TCDD or TCDD) in 1993 when the Committee concluded "...that there was insufficient evidence for a causal link, but it would be prudent at present to regard TCDD as a possible human carcinogen." This was a similar conclusion to that reached by the IARC* in 1987 where TCDD was classified in group 2B (ie possibly carcinogenic to humans). The IARC have undertaken a further review of the literature (and have now concluded that TCDD should be considered as a definite human carcinogen (ie group 1 carcinogen).(1) The conclusion reached by the IARC Working Group may have potential public health implications with respect to the hazard and risk
assessment of TCDD and also with respect to other polychlorinated dibenzo dioxins (PCDDs) and polychlorinated dibenzo furans (PCDFs) which are widely dispersed environmental contaminants.

ii) It was therefore important for the Committee to reconsider its previous conclusion. The Committee
reviewed the IARC monograph and specifically the critical epidemiology studies on TCDD cited in the monograph, ie those investigations which considered individuals whose exposure to TCDD occurred under industrial situations and was documented to be substantially higher than background exposures from environmental sources of TCDD.(2-15) The Committee also considered the literature on animal studies
and investigations of the carcinogenic mechanism of TCDD in animals as cited in the monograph and a number of recent papers on the toxicological mechansisms of TCDD.(16-26)

Conclusions

iii) The Committee reached the following conclusions which were finalised at the meeting of May 1998.

Epidemiological data

iv) There is limited epidemiological evidence in humans for carcinogenicity of 2,3,7,8-TCDD. The Committee reviewed the available epidemiological studies published since the previous COC review completed in 1993. It was noted that the new studies were predominantly comprised of updates of cohort studies previously reviewed in 1993. The Committee was also aware of a publication reporting the most recent results from the IARC multi-country study. (12) Members agreed that all of the limitations previously noted in 1993 applied to the current studies namely; 1) mixed chemical exposures which included some known carcinogens, 2) exposure to PCDDs was due to their presence as low level contaminants of other chemicals such as chlorophenoxy acid herbicides to which the cohorts had much greater exposure and 3) the lack of data to infer an association with any specific cancer.

v) The Committee agreed that the approach used by the IARC Working group to evaluate the epidemiological data on TCDD was satisfactory and the monograph clearly identified the critical studies which all involved the most highly exposed cohorts. The IARC working group calculated a relative risk
estimate for total cancer of 1.4 (95% CI 1.2-1.6)). The Committee agreed that since its previous evaluation, there was considerably more epidemiological data now available and this was consistent with an increase in overall cancer mortality but concluded that, since no consistent significant association between TCDD and any specific cancer was evident, the epidemiological data should be considered as indicating limited* evidence of cancer in humans, ie the same conclusion as that reached by the IARC Working Group.

Animal studies and data on mechanism(s)

vi) There is sufficient* evidence for carcinogenicity of 2,3,7,8-TCDD in animals. The mechanism of carcinogenicity in animals has not been established for individual tumour sites but the available evidence suggests that this might involve tumour promotion. TCDD induced gene expression in laboratory animals is mediated through binding to the Ah receptor protein and this includes the induction of genes involved
with control of cell replication but there is no convincing evidence to associate these particular effects with the induction of specific tumours. The COM is to review mutagenicity data on TCDD.

vii) The IARC working group considered three supporting pieces of evidence when considering their final recommendation that TCDD should be regarded as a definite human carcinogen (ie category 1). The Committee agreed the following response regarding the supporting statements;

Statement 1. TCDD is a multi-site carcinogen in experimental animals that has been shown by several lines of evidence to act through a mechanism involving the Ah receptor.

With regard to statement 1, the Committee agreed that TCDD is a multi-species carcinogen in laboratory animals. The Committee concluded that the available evidence was not sufficient to draw any definite conclusions with regard to the mechanism of carcinogenicity in laboratory animals and it was not possible to comment on the role of the Ah receptor in this regard.

Statement 2. This receptor is highly conserved in an evolutionary sense and functions in the same way in humans as in experimental animals.

With regard to statement 2, the Committee agreed that there was considerable sequence homology between Ah receptor proteins isolated from laboratory animals and humans. However, there was no adequate information with which to compare Ah induced gene expression in laboratory animals and
humans or to identify all of the genes induced in humans. It was therefore not possible to draw any definite conclusions on the potential significance for carcinogenesis of Ah receptor-mediated gene induction in humans.

Statement 3. Tissue concentrations are similar both in heavily exposed human populations in which an overall increased cancer risk was observed and in rats exposed to carcinogenic dosage regimens in bioassays.

With regard to statement 3, the Committee considered that the comparison of TCDD tissue concentrations using data from rat cancer bioassays and human populations with heavy occupational exposures to PCDD mixtures was inappropriate. Members agreed that such comparisons took insufficient account of the relative differences in toxicokinetics of TCDD between laboratory animals and humans or the different exposure regimes under which the data were obtained. Members agreed that the comparison of life-time exposure in rodents with high level occupational exposure which occurred for
varying and proportionately shorter periods in the IARC analysis was not appropriate.

Overall Conclusion

viii) Members considered that TCDD was a potent carcinogen in laboratory animals. However, the information from the most heavily occupationally exposed cohorts suggested there was at most, only a weak carcinogenic effect in these individuals. The Committee concluded that there were insufficient epidemiological and toxicological data on TCDD to conclude a causal link with cancer in humans, but it
would be prudent to consider TCDD as a 'probable weak human carcinogen'.

(* The World Health Organisation International Agency for Research on Cancer (IARC) definitions of terms "limited" evidence of carcinogenicity to humans and "sufficient" evidence of carcinogenicity in animals have been used by the COC in these conclusions. These can be consulted in the preamble to individual monographs.)

References

1. IARC (1997). Monographs on the evaluation of carcinogenic risks to humans. Volume 69, Polychlorinated dibenzo-para-dioxins and polychlorinated dibenzofurans, Lyon, pp 33-343.

2. Collins JJ, Strauss ME, Levinskas GJ and Conner PR. The mortality experience of workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin in a trichlorophenol process accident. Epidemiology, (1993), 4,(1), 7-13.

3. Fingerhut MA et al . Cancer mortality in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. The New England Journal of Medicine, (1991), 324, (4), 212-218.

4. Ott GA and Zober A. Cause specific mortality and cancer incidence among employees exposed to 2,3,7,8-TCDD after a 1953 reactor incident. Occupational and Environmental Medicine (1996), 53, 606-612.

5. Manz A, Berger J, Dwyer JH, Flesch-janys D, Nagel S and Waltsgott. Cancer mortality among workers in chemical plant contaminated with dioxin. The Lancet (1991), 338, (8773), 959-964.

6. Flesch-Janys D, Berger J, Gurn P, Manz A, Nagel S, Waltsgott H and Dwyer JH. Exposure to polychlorinated dioxins and furans (PCDD/F) and mortality in a cohort or workers from a herbicide producing plant in Hamburg, Federal Republic of Germany. American Journal of Epidemiology, (1995), 142, (11), 1165-1175.

7. Flesch-Janys D. Erratum. American Journal of Epidemiology, (1996), 144, (7), 716.

8. Swaen GMH. Letter to editor.American Journal of Epidemiology, (1997), 146, (4), 362-363.

9. Becher H, Flesch-Janys D, Kauppinen T, Kogevinas M, Steindhorf K, Manz A and Wahrendorf J.Cancer mortality in German male workers exposed to phenoxy herbicides and dioxins. Cancer Causes
and Control, (1996), 7, 312-321.

10. Coggon D, Pannett B and Winter P. Mortality and incidence of cancer at four factories making phenoxy herbicides. British Journal of Industrial Medicine, (1991), 48, 173-178.

11. Bueno de Mesquita HB, Doornbos G, van der Kuip DAM, Kogevinas M and Winklemann R.Occupational exposure to phenoxy herbicides and chlorophenols and cancer mortality in the Netherland. American Journal of Industrial Medicine, (1993), 23, 289-300.

12. Kogevinas M et al. Cancer mortality in workers exposed to phenoxy herbicides, chlorophenols, and dioxins. American Journal of Epidemiology, (1997), 145, (12), 1061-1075.

13. Kogevinas M et al. Soft tissue sarcoma and non-Hodgkin's lymphoma in workers exposed to phenoxy herbicides, chlorophenols, and dioxins: Two nested case-control studies. Epidemiology, (1995), 6, 396-402.

14. Bertazzi PA, Zocchetti C, Guercilena S, Consonni D, Tironi A, Landi MT, and Pesatori AC. Dioxin exposure and cancer risk. A 15 year mortality study after the Seveso accident. Epidemiology, (1997) 8,(6), 646-652.

15. Landi M, Needham LL, Lucier G, Moccarelli P, Bertazzi PA and Caporaso N. Concentrations of dioxin 20 years after Seveso. The Lancet, 349, June 21, 1997, 1811.

16. Safe S. Polychlorinated Biphenyls (PCBs), Polychlorinated Dibenzo-p-Dioxins, and related compounds: Environmental and mechanistic considerations which support the development of Toxic Equivalency Factors (TEFs). Critical Reviews in Toxicology,(1990), 21, (1), 51-,

17. Schiestl RH, Aubrecht J, Yap WY, Kandikonda S and Sidhom S. Polychlorinated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin induce intrachromosomal recombination in-vitro and in-vivo. Cancer Research, (1997), 57, 4378-4383.

18. Rowlands JC and Gustafsson JA. Aryl hydrocarbon receptor-mediated signal transduction. Critical
Reviews in Toxicology, (1997), 27, (2), 109-134.

19. Blankenship A and Matsumura F. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) causes an Ah
receptor-dependent and ARNT-independent increase in membrane levels and activity of p60Src. Environmental Toxicology and Pharmacology, (1997), 3, 211-220.

20. Rininger JA, Stoffregen DA and Babish JG. Murine hepatic p53, RB and CDK inhibitory protein
expression following acute 2,3,7,8-terachlorodibenzo-p-dioxin exposure. Chemosphere, (1997), 34,(5-7),1557-1568.

21. Kharat I and Saatcioglus F. Antiestrogenic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin are mediated by direct transcriptional interference with the liganded estrogen receptor. The Journal of Biological
Chemistry, (1996), 271, (18), 10533-10537.

22. Sewall CH. Lucier GW, Tritscher AM and Clark GC. Carcinogenesis, 14, (9), 1885-1893. TCDD-mediated changes in hepatic epidermal growth factor receptor may be critical event in hepatocarcinogenic action of TCDD. Carcinogenesis, (1993), 14, (9), 1893-1993.

23. Worner W and Schrenk D. Influence of liver tumour promoters on apoptosis in rat hepatocytes induced by 2-acetylaminofluorene, ultraviolet light or transforming growth factor 11. Cancer Research,(1993), 56, 1271-1278.

24. Kohn MC, Sewall CH, Lucier GW and Portier CJ. A mechanistic model of effects of dioxin onthyroid
hormones in the rat. Toxicology and Applied Pharmacology, (1996), 165, 29-48.

25. Hays SM, Aylward LL, Karch NJ and Paustenbach DJ. The relative susceptibility of animals and humans to the carcinogenic hazard posed by exposure to 2,3,7,8-TCDD: An analysis using standard and internal measures of dose. Chemosphere, (1997), 34, (5-7), 1507-1522.

26. Roberts RA, Nebert DW, Hickman JA, Richburg JH and Goldsworthy TL. Pertubation of the mitosis/apoptosis balance: A fundamental mechanism of toxicology. Fundamental and Applied Toxicology, (1997), 38, 107-115.