Toxicology of HCBD
5. There is very little information on the toxicological effects of HCBD derived from studies on humans. Consequently, an assessment of the possible risks to human health has to be based on laboratory and animal data. However, most animal toxicity studies on HCBD have been conducted using oral exposure and there are few studies of exposure by inhalation, the prime route of exposure for residents at Weston.
6. The results of studies of repeated oral administration indicate that HCBD can cause damage to the kidneys at doses of 0.5 milligrams/kilogram body weight per day (mg/kg b.w. per day) and above in female mice1 and at doses of 2 mg/kg b.w. per day and above in both sexes of rats.2 Damage to other tissues (liver, nervous system) has been reported at a higher dose of 20 mg/kg b.w. per day in rats.2 In reproduction studies at this dose foetal toxicity, predominantly manifested as retardation of foetal growth, was also recorded in rats.3 However, these effects were attributed to maternal toxicity because adverse developmental effects were not induced at doses that were not toxic to the dam. Limited information from the animal studies indicates that exposure by inhalation results in the same toxic effects, with the kidney being the prime target organ.
7. Thresholds for each of these adverse effects have been demonstrated in several studies. The Committee considered that the response in the kidneys of mice is the most sensitive indicator of the toxicity of HCBD but that the response of one female mouse dosed with 0.2 mg/kg b.w. per day for 13 weeks1 was not sufficient evidence to warrant the use of a lower figure for a No Observed Adverse Effect Level (NOAEL). Therefore, the Committee considered that, for non-carcinogenic effects, the NOAEL is 0.2 mg/kg b.w. per day.4,5
8. Members of our sister committee, the Committee on Mutagenicity of Chemicals in Food, Consumer Products and the Environment (COM) have reviewed the mutagenicity of HCBD. There are in vitro data, mainly from studies using Salmonella TA100, that indicate that HCBD has mutagenic potential.6,7 Negative results have been reported from in vivo assays in bone marrow 8,9 but these were inadequate to draw definite conclusions. COM members considered that further in vivo studies were needed, particularly in the kidney, before any definite conclusions could be drawn. On the data currently available it would be prudent to assume that HCBD is an in vivo somatic cell mutagen.
9. A carcinogenic response has been seen in the kidneys of rats in a study in which HCBD was administered continually in the diet for two years at a dose of 20 mg/kg b.w. per day (the highest dose tested). No tumours were observed in the kidneys of male or female rats administered doses of 2 mg/kg b.w. per day or lower.2
10. In view of the advice from the COM that HCBD should be regarded as an in vivo mutagen the COT were unable to establish a safe level in relation to cancer or to identify a tolerable daily intake (TDI) for HCBD.
11. From animal studies, the Committee agreed that a NOAEL of 0.2 mg/kg b.w. per day had been established for the non-carcinogenic effects of HCBD.
12. The Committee considered that, in order to estimate the concentration in air that would result in humans inhaling a dose of 0.2 mg/kg b.w. per day, it was necessary to make the following assumptions:
- the toxicity of HCBD following inhalation exposure is essentially the same, both qualitatively and quantitatively, as the toxicity of HCBD following oral exposure;
- there are no significant differences in the extent of absorption of HCBD by either route; and
- a 60 kg adult would inhale 20 cubic metres (m3) of air per day.
On this basis the Committee considered that, as an approximation, a dose of 0.2 mg/kg b.w. per day would correspond to the continuous inhalation of air containing 0.6 mg/m3 of HCBD, equivalent to an air concentration of about 60 ppb.
13. In view of the evidence that there are qualitative similarities between humans and animals in the way that HCBD is distributed and metabolised in the body, the Committee considered that continuous exposure to a concentration of HCBD in air of less than 0.6 ppb (i.e. the Margin of Exposure below 60 ppb is at least 100) can be regarded as being without appreciable adverse health effects in respect of non-carcinogenic and reproductive effects.
14. In respect of concerns about a potential carcinogenic effect, the Committee noted that exposures to less than 0.6 ppb HCBD were 10,000 times lower than the equivalent dose of HCBD which, when fed daily throughout a lifetime to rats, had resulted in kidney tumours. The Committee considered therefore that the carcinogenic risk at these low exposure levels was minimal and was not of appreciable health concern. However, given the uncertainties in the data, the Committee considered that exposure should be reduced to as low a level as reasonably practicable (ALARP).
15. The Committee was informed that health studies are being undertaken of exposed residents of Weston 10 and members of the ICI workforce.11 There is also a proposal to develop a physiologically-based pharmacokinetic model for HCBD exposure.11 In addition, the Committee was informed that a technique is being developed to allow analysis for HCBD at parts per trillion concentrations in air. The Committee welcomed this information and considered that the results of these studies should inform a further review by the Committee, in due course, of its conclusions on the health significance of low-level exposures to HCBD.
COT Statement 2000/04
1. Yang RSH, Abdo KM, Elwell MR, Levy AC, Brendnecke LH (1989). Subchronic toxicology studies of hexachloro-1,3-butadiene (HCBD) in B6C3F1 mice by dietary incorporation. J Environ Pathol Toxicol Oncol; 9:323-332.
2. Kociba RJ, Keyes DG, Jersey GC, Ballard JJ, Dittenbov DA, Quast JF, Wade CE, Humiston CG, Schwetz BA (1977). Results of a 2 year chronic toxicity study with HCBD in rats. Am Ind Hyg Assoc J; 38:589-602.
3. Schwetz BA, Smith FA, Humiston CG, Quast JF, Kociba RJ (1977). Results of a reproductive toxicity study in rats fed diets containing HCBD. Toxicol Appl Pharmacol; 42:382-398
4. International Program on Chemical Safety (1994). Environmental Health Criteria No. 156. Hexachlorobutadiene. Geneva:IPCS/World Health Organization.
5. WHO (1993). Guidelines for drinking water quality. Volume 1, pp 73-74, Hexachlorobutadiene. Geneva:World Health Organization.
6. Wild D, Schultz S, Reichert D (1986). Mutagenicity of the mercapturic acid and other S-containing derivatives of HCBD. Carcinogenesis; 7:431-434.
7. Vamvakas S, Kardowich FJ, Dekant W, Neudecker T, Henschler D (1988). Mutagenicity of HCBD and its S-conjugates in the Ames test - role of activation by the mercapturic acid pathway and its nephrocarcinogenicity. Carcinogenesis; 9:907-910.
8. Mailhes JB, Schwetz BA, Patton PC, Lisowe RW (1974). Cytogenetic effects of HCBD on rat bone marrow. Unpublished study, Dow Chemical Co., Midland, Michigan, USA.
9. NIOSH (1981). Tier 2 study of 13 priority compounds, report on HCBD. NIOSH Report No PB83 152397. Cincinnati, Ohio, USA.
10. Dr B Staples (North Cheshire Health Authority). Personal communication.
11. Dr D Makepeace (Occupational Physician, ICI). Personal communication.