The Effects of 1,3-Butadiene on Human Health

13. Evidence of the hazard of 1,3-butadiene comes from two main sources: firstly, studies of human populations exposed in the workplace and, secondly, from investigations carried out in laboratory rats, mice and monkeys. The Panel put greatest weight on data derived directly from human studies; however, compared with benzene, fewer human data are available and greater emphasis has had to be placed on results from laboratory investigations. The animal data are consistent in showing 1,3-butadiene to be a potent carcinogen and to act, through another chemical to which it is converted in the body, on the genetic material of cells as a genotoxic carcinogen.
14. The Panel recognise that extrapolation from the results of animal experiments to effects in man is difficult and involves uncertainties. There are also difficulties in extrapolating from studies of workers exposed in the past to the general population of today. The levels to which workers may be exposed are very much higher than those in ambient air; for example, a worker could be exposed intermittently to levels of up to 10,000 ppb (the United Kingdom workplace maximum exposure limit) compared with an hourly average of about 20 ppb during a severe short-term atmospheric pollution episode in a city. There is no feasible study in man which will show a measurable effect on health of the relatively low levels occurring in the general atmosphere.
15. The data on absorption, distribution, metabolism (that is, biological and/or chemical breakdown) and elimination of 1,3-butadiene in humans are limited but some information is available from laboratory studies on animals and it is possible to draw some general conclusions. Inhalation studies have indicated that 1,3-butadiene is absorbed through the lungs and can be detected in all tissues which have been examined. Studies comparing uptake in mice, rats and monkeys have shown uptake to be greatest in mice and least in monkeys. 1,3-Butadiene and the main chemical to which it is converted in the body, an epoxide (1,2-epoxybut-3-ene), are eliminated in exhaled air of mice and rats.
16. The metabolism of 1,3-butadiene has been studied in several animal species, and also in tissues derived from them. Differences exist between species and the formation of the dangerous chemicals to which it is converted (epoxides) is most rapid in mice. Laboratory studies have shown that human tissues can produce epoxide metabolites; however, at low doses, the relative capacity of tissues from different species to metabolise 1,3-butadiene is unknown.
17. Short-term human exposures to very high concentrations (several million ppb) of 1,3-butadiene, including experimentation on volunteers conducted in the 1940s before its carcinogenic potential was suspected, have caused irritation of the eyes, nose, throat and skin. Investigations of workers in Eastern Europe exposed occupationally to high concentrations of 1,3-butadiene have shown them to have been at risk of a variety of disorders, including diseases of the blood and nervous system. These studies did not take account of other possible harmful factors. The general public in the United Kingdom would be exposed to much lower concentrations, although for longer periods.
18. The effect of long-term exposure which is of most concern is the induction of cancers of the lymphoid system and blood-forming tissues, lymphomas and leukaemias. An increase in the risks of developing these types of cancers has been reported in groups of workers in the United States from the 1,3-butadiene manufacturing industry and from the styrene-butadiene rubber manufacturing industry. Exposures of rats and mice to high inhaled concentrations of 1,3-butadiene for all or most of their lifetimes have shown similar effects, as well as an increased mortality from other types of malignant disease. Species differences in susceptibility to the development of malignant disease have been demonstrated; mice, particularly females, are sensitive to the carcinogenic effects of 1,3-butadiene with an increase in tumours being noted after long duration exposure to levels of, and in excess of, 6,250 ppb. This increased susceptibility may, in part, be due to the differences in uptake and metabolism of 1,3-butadiene in mice as compared with other animals which were noted previously.
19. Various laboratory studies examining the mode of action of 1,3-butadiene and some of its metabolites have been carried out. 1,3-Butadiene damages the genetic material of cells in various ways and these genotoxic effects indicate that it may cause malignant disease after very small exposures. The Panel have taken the view, as with benzene, that while this could be strictly interpreted as meaning that there is no safe level to which people can be exposed, a more realistic view is that the risks become progressively smaller as the cumulative exposure of an individual is reduced and that there is a level at which increased risks attributable to 1,3-butadiene are exceedingly small and unlikely to be detectable by any practicable method.
20. Further problems in extrapolating risk from groups of industrial workers to the general population relate to the size and make-up of the industrial group studied. In the work reported in the medical literature, the industrial groups (often called 'cohorts', that is defined groups of workers followed forward over time in order to estimate their risks of death from various diseases) have ranged in size from about 2,500 - 12,000. Lymphomas and leukaemias are relatively uncommon in the general population of the United Kingdom, occurring in about 1 person in 2,800, and it is often difficult (on present knowledge) to exclude the possibility that small excesses of cases are chance occurrences. Thus, the smaller the cohort, the greater the disease-causing effect has to be in order for it to be detected. However, in one of the cohorts the exposure histories of workers who had died of lymphoma or leukaemia were compared with those of control workers without these diseases, matched for factors such as age, year of employment and factory. The results showed those who had died of lymphoma or leukaemia to have had a substantially greater occupational exposure to 1,3-butadiene than had the control workers.
21. An important point the Panel have considered in recommending a Standard concerns the differences between past industrial cohorts and the general population. The former generally comprised fit males, young and middle-aged, whereas the general population also includes children, pregnant women, the elderly and the sick, some of whom may be particularly sensitive to toxic chemicals. Industrial workers are potentially exposed to relatively high concentrations for perhaps 8 hours per day, five days weekly for 40 years, whereas the general population is exposed to much lower concentrations, but throughout their lifetimes.
22. The Panel have examined published reports of studies of lymphomas and leukaemias in groups of workers exposed to 1,3-butadiene. None of these provided information on measured exposures of workers who had died from these cancers; however, attempts have been made to categorise workers' exposure using job description data (see Table 2). Exposure data for people currently exposed to 1,3-butadiene and doing jobs having the same job description as those identified as being at particular risk from 1,3-butadiene were also available (see Table 3). Current exposures in these jobs are likely to be lower than in the past owing to changes in work practices and improved controls. For example, the American Conference of Governmental Industrial Hygienists' threshold limit value³ for exposure to 1,3-butadiene over an 8-hour working day in a 40-hour working week was, until 1984, 1,000,000 ppb (as a time-weighted average), as compared with the present value of 10,000 ppb and a proposal that it should be further reduced to 2,000 ppb. Assuming that the job description applied to the same type of work being done now as formerly and given that current workplace levels are lower than in the past, thus providing an inbuilt safety factor, the Panel used the current exposure data to obtain a level of exposure for the groups of workers identified as probably not having been at increased risk of developing these cancers. Consideration of these data led the Panel to conclude that it was unlikely that an excess risk of lymphomas or leukaemias would be detectable at exposures below about 1,000 ppb. We note, however, the relative weakness of the available information on human exposures, even compared with that available for benzene, and therefore acknowledge the uncertainty surrounding this figure.

Table 2 Summary of recent 1,3-butadiene epidemiological studies

Authors	Study	Number of subjects	Cancer type*	Number of deaths	SMR**	95%CIý
Downs, Crane & Kim 1987 updated by Divine 1990	1,3-Butadiene production plant, Port Neches, Texas process workers 1943-1979 (cohort study)	2582	Lymphatic and haematopoietic	25	130	84-192
			(Lymphosarcoma and reticulosarcoma)	(9)	(229)	(104-435)
Meinhardt et al. 1982	Styrene-butadiene rubber facility, Port Neches, Texas, production workers, Plant A, 1943-1976 (cohort study)	1662	Lymphatic and haematopoietic	9	155	71-295
			(leukaemia, aleukaemia)	(5)	(203)	(66-472)
		All deaths occurred in men first employed between 1943 and 1945 after which the process changed from batch to continuous feed operation
Meinhardt et al. 1982	Styrene-butadiene rubber facility, Port Neches, Texas, production workers, Plant B, 1950-1976 (cohort study)	1094	Lymphatic and haematopoietic	2	78	10-283
			(leukaemia, aleukaemia)	(1)	(101)	(3-563)
Matanoski, Santos-Burgoa & Schwartz 1990	Styrene-butadiene rubber facilities, United States and Canada, 1943-1982 (cohort study)
	production workers:	3124	All lymphopoietic (other lymphatic)	19 (9)	146 (260)	88-227 (119-494)
	maintenance workers:	3271		14 (2)	75 (39)	41-126 (5-141)
	utility workers:	457		5 (2)	203 (313)	66-474 (62-695)
	others:	2867		12 (2)	87 (54)	45-152 (7-196)
Cowles et al. 1994	1,3-Butadiene production plant, Deer Park Manufacturing Complex, interrupted production; production workers, 1948-1989 (cohort study)	614	Lymphatic and haematopoietic	0	-	-
Authors	Study	Number of subjects	Cancer type*	Number of deaths	OR**Ý	95%CIý
Santos-Burgoa et al. 1992	Styrene-butadiene rubber facilities, United States and Canada, 1943-1982 (nested case-referent study)	59 cases matched with 193 controls	All lymphohaematopoietic	59	2.12	0.86-5.18
			(leukaemia)	(26)	(7.39)	(1.32-41.3)
* Despite the diversity of terms listed here all of them refer to different categories of lymphomas and/or leukaemias. The descriptions and figures in parentheses represent sub-groups of the main category. ** SMR: Standardised Mortality Ratio, the ratio of the observed number of deaths in the occupationally exposed cohort to the expected number of deaths in a control group of this size of unexposed persons multiplied by 100. For control groups the studies have used either the national populations or workers in other industries. Ý OR: Odds Ratio, the odds in favour of exposure amongst cases to the odds in favour of exposure amongst controls. Values above 1.0 indicate a greater risk of exposure to 1,3-butadiene in the cases. ý CI: Confidence Interval, the 95% CI is the range in which, allowing for variability in study populations, there is a 95% chance of the true result falling. If, in the Table, the value 100 is not included in the 95% CI shown for the SMR then there is only a 1 in 40 chance that the increase in leukaemia/lymphoma deaths is an erroneous result (p < 0.025). Similarly, if the value 1.0 is not included in the 95% CI shown for the OR then there is only a 1 in 40 chance that the greater exposure of the cases is an erroneous result.

Table 3 Exposure profiles (1990) of U.S. workers in 1,3-butadiene production identified in the epidemiological studies as not being at increased risk of developing lymphomas or leukaemias*

Industry	Worker category	Percentage exposed to:
		<1000 ppb	<2000 ppb	<5000 ppb
Crude 1,3-butadiene production	Maintenance	85%	91%	96%
1,3-Butadiene monomer production	Maintenance	85%	91%	96%
1,3-Butadiene polymer + other	Maintenance	85%	91%	96%
	Utilities	93%	96%	100%
* Compiled from Department of Labor, Occupational Safety and Health Administration, 1990.