UK government policy on dioxin

["david bell" <burnt_paper@hotmail.com>]

The UK government bodies for assessing toxicity and mutagenicity are now on 
the web.
Committee on carcinogenicity
http://www.doh.gov.uk/coc.htm
Committee on toxicity
http://www.doh.gov.uk/cot.htm

These pages contain some detailed analysis of decisions on various 
chemicals, and why they were made, e.g.

on chlorinated drinking water
http://www.doh.gov.uk/cot/drink.htm

whether dioxin is a human carcinogen
http://www.doh.gov.uk/tcdd.htm




for info, the dioxin statement
**************
COMMITTEE ON CARCINOGENICITY OF CHEMICALS IN FOOD, CONSUMER PRODUCTS AND THE
ENVIRONMENT


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
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(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
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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
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Winklemann R.Occupational
exposure to phenoxy herbicides and chlorophenols and cancer mortality in the 
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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
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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
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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 
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21. Kharat I and Saatcioglus F. Antiestrogenic effects of 
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(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 
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23. Worner W and Schrenk D. Influence of liver tumour promoters on apoptosis 
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