TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin)
COM statement COM/99/S2 - May 1999
The following statement was agreed under matters arising at the May 1999
meeting of the Committee.
Introduction
1. There are 75 possible chlorinated polychlorinated-para-dioxins
(PCDDs) and 135 possible polychlorinated-para-dibenzofurans (PCDFs). A
number of these substances (congeners), predominantly the tetra- through
to octa-congeners may be found as trace contaminants in food. The toxicological
properties and potencies of PCDDs and PCDFs mixtures have been estimated
from the available information on TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin)
through the use of toxic equivalency factors (TEFs). TCDD thus serves
as a model compound for the risk assessment of other PCDD/PCDF mixtures.(1)
2. PCDDs are produced as a trace contaminant during the manufacture
of many organochlorine compounds such as 2,4,5-trichlorophenol (TCP),
chlorophenoxy herbicides (2,4,5-T), hexachlorophene, chlorodiphenyl ether
herbicides), and during certain industrial processes such as pulp bleaching
using chlorine gas. They are also produced in a number of thermal reactions
such as the incineration of municipal waste, sewage sludge, PVC as well
as from automobile emissions. The highest exposures have predominantly
occurred under occupational settings, often following accidental release,
the exception being the large widespread release of TCDD to the environment
with population exposure following the Seveso incident in 1976.
3. The IARC (International Agency for Research on Cancer) concluded in
1997 that TCDD should be regarded as a known human carcinogen and thus
classified as Group 1.(2) Previously it had been classified as Group 2A
(probable human carcinogen). This change prompted the Department of Health
to request COC to review their earlier conclusion. The COC concluded in
1998 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
IARC workinggroup concluded that the "experimental data indicated
that 2,3,7,8-TCDD and probably other PCDDs and PCDFs are not direct-acting
genotoxic agents and that TCDD is considered a non-genotoxic substance."
The previous COM evaluation of TCDD was completed in 1987 and it is therefore
timely for the committee to reconsider its previous conclusions.
COM conclusions from 1987
4. The COM considered all the available information in 1987 and drew
the following conclusions.
5. TCDD does not produce gene-mutations in Salmonella assays, but there
is some evidence from higher eukaryotes (yeasts) and a mammalian cell
assay that the compound has some potential for producing gene mutations
although the mammalian cell assay has not been repeated. However negative
results were obtained in the sex linked recessive lethal assay in Drosophila.
6. There is no convincing evidence that TCDD has clastogenic properties.
Negative results were also obtained in studies to investigate the compound's
ability to produce sister chromatid exchanges (SCEs) in vitro and
in vivo, and also unscheduled DNA synthesis (UDS) in rat hepatocytes,
indicating that TCDD does not produce DNA damage in these systems.
7. These results suggest that although TCDD may have some mutagenic potential
in yeast systems, on balance negative results were obtained, and it is
unlikely that the carcinogenicity observed in the rodent assays is due
to a mutagenic mechanism. There is limited evidence from cell transformation
assays that TCDD has tumour promotor activity.
8. The very limited data available on the other chlorinated dibenzo dioxins
and dibenzo furans precludes any conclusions being drawn about the mutagenic
potential of these compounds.
1999 COM review
9. The Committee needed to update its advice to enable a COC/COM statement
on the current position to be agreed. In this regard, the Department of
Health Toxicology Unit at Imperial College of Science, Technology and
Medicine (ICSTM) was asked to provide a review of the literature published
since 1990 on the TCDD regarding mutagenicity data. The authors noted
that the majority of studies conducted since 1987 had yielded negative
results. The report highlighted a number of investigations where further
consideration might be required.
10. The Committee agreed that negative results had been obtained in the
in-vitro mutagenicity tests conducted in Salmonella and in L5178Y tk+/tk-
cells mouse lymphoma cells.(3, 4) However TCDD induced micronuclei formation
had been reported in one study using human lymphocytes and the cytochalasin
B technique.(5) The same research group had also noted sister chromatid
exchange (SCE) in a subsequent publication.(6) Members commented that
it was not possible to draw any conclusions based on these results particularly
in view of the unusually long incubation period of 71 hours prior to harvesting
the cells. The Committee agreed that a repeat test would be desirable
in order to validate the method used in these investigations.
11. The Committee agreed that negative results had been obtained in mouse
hepatocytes following dosing of animals with up to 150 µg/kg (i.p).(7)
No increase in SCEs in peripheral blood lymphocytes was noted in Rhesus
monkeys, 2 years post administration of a diet containing 25 ppt TCDD
for 4 years.(8) However, a small, but statistically significant increase
in SCEs in peripheral blood lymphocytes had been documented in a limited
study in rats given weekly gavage doses of 5 µg/kg for 2 weeks but
not at 0.5 µg/kg.(9) Evidence of TCDD induced single stand DNA breaks
in peritoneal lavage cells had been documented in rats given a single
oral dose of 25 µg/kg bw up to 100µg/kg.(10) In addition,
a positive result had been reported in a deletion recombination spot test
(11) but not in a separate study which used a similar dosing regime.(12)
Members considered that no weight could be attached to this investigation
in view of the limited study design, the concerns previously expressed
by Members regarding these tests and the negative findings reported in
a mouse spot test by a separate research group.
COM Conclusions
12. The Committee agreed the following conclusions.
(a) "In studies published since 1987, TCDD has continued to give
largely negative results in tests for several different genetic endpoints,
such as DNA damage, gene mutations, sister chromatid exchange and cell
transformation. In a few studies TCDD has given a positive or equivocal
result, often using assays with either highly non-standard or sub-optimal
design. Currently the weight of the available experimental data continue
to indicate that TCDD is not a genotoxic agent."
(b) The Committee wished to continue to monitor any further genotoxicity
publications on TCDD.
References
1. Safe S (1990). Polychlorinated biphenyls, dibenzo-p-dioxins (PCDDs),
dibenzofurans (PCDFs) and related compounds: environmental and mechanistic
considerations which support the development of toxic equivalency factors
(TEFs). CRC Critical Reviews in Toxicology, 21, 51-88.
2. IARC (1997). IARC Monographs on the evaluation of carcinogenic risks
to humans. Polychlorinated dibenzo-para- dioxins and polychlorinated-para-dibenzofurans.
Volume 69, pp1-666, WHO, Lyons, France.
3. Blevis RD (1991). 2,3,7,8-tetrachlorodibenzo-p-dioxin in fish from
Pigeon River of Eastern Tennessee, USA, its toxicity and mutagenicity
as revealed by the Ames test. Arch Environ Contam Toxicol, 20, 366-370.
4. McGreegor DB et al (1991). Responses of the L5178Y mouse lymphoma cell
forward mutation assay. 527 coded chemicals. Environ Mol Mut, 17, 196-219.
5. Nagayama J and Masuda Y (1993). Effects of 3-methylsulphonyl-4,5,3,4-
tetrachlorobiphenyl and 7,8-benzoflavone on aryl hydrocarbon hydroxylase
activities of murine hepatic microsomes prepared from inbred strains with
different Ah responsiveness. Fukuoka Acta Med, 84, 195-202.
6. Nagayama J et al (1995). Effect of 2,3,4,7,8-pentachlorodibenzofuran
and its analogues on induction of sister chromatid exchanges in cultured
lymphocytes. Fukuoka Acta Med, 86, 184-189.
7. Brooks Al et al (1988). The cytogenetic and hepatotoxic effects of
dioxin on mouse liver cells. Cell Biol Toxicol, 4, 31-40.
8. Lim M et al (1987). Effect of chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin
on sister chromatid exchange levels in peripheral lymphocytes in Rhesus
Monkey. Cell Biol Toxicol, 3, 279-284.
9. Mustonen J et al (1989). Effects of commercial chlophenate, 2,3,7,8-TCDD,
and pure phenoxyacetic acids on hepatic peroxysome proliferation, xenobiotic
metabolism and sister chromatid exchange in the rat. Arch Toxicol, 63,
203-208.
10. Alsharif NZ et al (1994). Stimulation of NADPH-dependent reactive
oxygen species formation and DNA damage by 2,3,7,8-tetrachlorodibenzo-p-dioxin
in rat peritoneal lavage cells. Arch Environ Contam Toxicol, 26, 392-397.
11. Schiestl RH et al (1997). Polychlorinated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin
induce intrachromosomal recombination in-vitro and in-vivo. Cancer Research,57,
4378-4383.
12. Fahrig R (1993). Genetic effects of dioxins in the spot test with
mice. Environ Health Perspect ,101, 257-261.
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