Institutet för miljömedicin

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1 Institutet för miljömedicin Karolinska institutet IMM-rapport 1/98 Risk assessment of carcinogenic air pollutants Katarina Victorin Stockholm 1998

2 Contents Summary... 3 Introduction... 4 Benzene ,3-Butadiene... 8 Dichloroethane... 9 Dichloromethane (Methylene Chloride) Ethene Ethylene oxide Formaldehyde Nitropropane Propene Styrene Tetrachloroethylene Trichloroethylene Vinyl chloride Acknowledgements References

3 Summary The Institute of Environmental Medicine (IMM) in Stockholm has recommended health-based guideline values (low-risk levels) for a number of carcinogenic air pollutants. In these risk assessments, mathematical extrapolation models have only been used for some genotoxic compounds or compounds giving rise to genotoxic metabolites. For other carcinogenic compounds a NOEL, LOEL/uncertainty factor approach has been used. In this paper the IMM risk assessments are commented upon, and comparisons are made with the corresponding risk assessments from US EPA and WHO. This report was originally presented at a seminar in December 1987 entitled "Carcinogen Risk Assessment: models and their applications". The seminar was arranged by the Swedish Toxicological Council and the proceedings will appear as a report from the National Chemicals Inspectorate. 3

4 Introduction At the Institute of Environmental Medicine (IMM), we have performed quantitative risk assessments of carcinogens at several occacions, mainly at the request of the Swedish Environmental Protection Agency to propose health based environmental guideline values for ambient air. In these cases the quantitative risk assessment is the final part of a larger effort that consists of collecting, reading, summarizing and evaluating the available literature. Some large epidemiological studies performed at the IMM have also led to quantitative risk estimates, such as one concerning the risk of lung cancer due to radon in homes. In this paper the basis for the risk assessment of some air pollutants will be discussed. When evaluating compounds for which there are epidemiological or animal data that can be used for quantitative risk estimates, the first main question is whether the compound should be regarded as genotoxic or not. In contrast to the policy of the US EPA, we have always considered this distinction to be vital, since low-dose risk extrapolations are only relevant for those carcinogens which apparently have a genotoxic mode of action. The theory of a mutational origin of tumour initiation is the basis for the simplified view that even at very low exposure levels there may be a risk, although infinitely small. This, in turn, is the basis for accepting low-dose extrapolation as a means of estimating the risk quantitatively. A threshold is assumed for other carcinogens that act at later stages in the tumour process, for example as tumour promoters, or in cases where the tumours can be expected to develop secondarily to cytotoxic damage. In practice, it is very diffucult to establish the mode of action for carcinogens, and many compounds show ambiguous results in different genotoxicity tests. Some events, like hormonal effects and effects through signal transduction, may also appear after exposure to very low doses. Still, we have only applied low-dose risk extrapolation for some genotoxic compounds (or metabolites). The recommended guideline values - the so-called low-risk levels - were in these cases set at the concentration that theoretically would result in an increased lifetime cancer risk of , assuming continuous inhalation of the air pollutant during a lifetime. For other carcinogens we have used a NOEL/LOEL uncertainty factor approach, just as for other toxic compounds. The recommended guideline values have in these cases been obtained by dividing the lowest concentration that resulted in a significant increase in tumours by a large uncertainty factor, usually For 4

5 some of these compounds other effects became the basis for the risk assessment and in those cases usually somewhat lower uncertainty factors were applied. For dose-response assessment and low-dose extrapolation, different models can be used. We have accepted the EPA linearized multistage model, and have in most cases used the unit risk figures found in the EPA IRIS database or other quantitative risk estimates from the literature. We have also made these kind of calculations ourselves, but in our final recommendations we have focused on internationally published risk figures. For some compounds, risk assessments based on pharmacokinetic models have been published. As different assumptions and input data may give varying results, it can be difficult to choose between different models. So far, we have only used the results of pharmacokinetic models to a very limited extent when recommending low-risk levels, although in principle such models may be more relevant when extrapolating the results from laboratory animal data to humans. We do not have a specific opinion on the dose conversion factor of (body weight) 3/4 from laboratory animals to humans that is recommended by the EPA, but we think that the relevance of this factor should be more closely investigated on a case by case basis. There might also be a difference in how to treat directly-acting carcinogens and those that need metabolic activation in this respect. For inhalation exposure the equivalent human dose can be calculated in several ways, and this matter should also be investigated in more detail. Maybe the easiest way of comparison, simply by the concentration in inhaled air, is as good a basis as more sophisticated models. We have applied the benchmark method for dose-response assessment of non-carcinogenic compounds, and have also developed a new model function for continuous data. The new EPA proposed guidelines advocates a change from the multistage model to one very much like the benchmark model, where the extrapolation is done linearily towards null from the lower 95% confidence limit of the dose corresponding to a 10% extra risk (P(D) - P(0)/1-P(0)) in tumour incidence. This approach must be compared to the multistage model concerning the resulting risk at low doses, such as the influence of different assumptions and options and the choice of mathematical model for the doseresponse assessment. 5

6 Table 1 is a summary of the IMM recommended guideline values (low risk levels) of a number of air pollutants. It should be observed that some of these risk assessments are more than ten years old, and that an update might lead to different conclusions. In some cases guideline values obtained both by lowdose extrapolation to a lifetime risk of and by the use of a NOEL/LOEL uncertainty factor approach are presented. When the latter are shown within brackets, it indicates that we have preferred the extrapolation model. All values refer to long-term averages unless otherwise specified in the text. The compounds will be commented on below. Table 1. Risk assessment and recommended guideline values by IMM (low-risk levels) for carcinogenic air pollutants. Substance Year Low-risk level (ppb) Extrapolation model Uncertainty (risk ) factor model Benzene (20) Butadiene (100) Dichloroethane Dichloromethane 1990? 100 (Methylene chloride) Ethene (2-40) Ethylene oxide (0.2-4) Formaldehyde Nitropropane Propene Styrene Tetrachloroethylene Trichloroethylene Vinyl chloride

7 Benzene Benzene is a common air pollutant in urban areas due to emissions from combustion sources and evaporation from gasoline. Benzene is an IARC Group 1 human carcinogen that has been the cause of leukemia in occupationally-exposed workers. An increased incidence of all lymphatic and hematopoietic cancer, and of multiple myeloma has also been demonstrated in some epidemiological studies. In animal experiments using mice and rats many different tumour forms have been induced. Concerning genotoxic effects, the mutagenicity of benzene has been difficult to demonstrate in vitro, although several of the benzene metabolites have caused mutations in different in vitro tests. However, benzene and its metabolites cause different forms of DNA damage. Benzene causes chromosomal damage both in vitro and in vivo, such as chromosome aberrations, sister chromatide exchages and micronuclei. Chromosome damage in lymphocytes has been recorded in several investigations of benzene-exposed workers. Consequently, we regard benzene as a genotoxic agent, and have based our risk assessment on quantitative extrapolation of the risk for leukemia in benzene-exposed workers. We relied on the most recent update of the so-called Pliofilm cohort at the time. Different regression analyses resulted in lifetime cancer risks in the range of per ppb. We chose the more conservative estimate, which would lead to a low-risk level of 0.4 ppb (1.3 µg/m 3 ), corresponding to a lifetime cancer risk of Our document was used as the basis for the updated WHO Air Quality Guidelines for Europe (in press). By then, mutations had been demonstrated in vivo, both in mice and in humans, thus strengthening a genotoxic mode of action. According to the WHO risk assessment, a lifetime risk of will result from µg/m 3 (mean 1.8), based on the same data as above. The EPA unit risk is based on the pooled results from older epidemiological studies, but yields a similar risk estimate (risk at 1 µg/m 3 ). 7

8 1,3-Butadiene Principally, 1,3-butadiene is used as a monomer in the manufacture of a wide range of polymers and co-polymers (e.g. styrene-butadiene rubber). Butadiene is also an ambient air pollutant due to its formation in different combustion processes, and it is found in emissions such as in wood smoke and automobile exhausts. It is classified by the IARC in Group 2A (probably carcinogenic to humans). Our document on butadiene is from 1986 and needs to be revised, because many important studies have been conducted since then. Although relatively little research had been done at that time concerning genotoxic effects, the risk assessment was made with an extrapolation model based on an inhalation study, that caused tumours in several different organs in rats and mice. We cited two unit risk estimates from the EPA, that would lead to a low risk level of ppb ( µg/m 3 ). The multistage model using mice data gave the higher risk estimate, and this one is still used by the EPA in the IRIS database, although there are newer cancer studies available for risk assessment. Mice are more sensitive to butadiene than rats due to a higher metabolic formation of epoxides. The metabolism of butadiene in humans seems to be more similar to that in rats than in mice, but because of the uncertainties involved, the WHO does not recommend a risk estimate or present a guideline value for butadiene in the updated Air Quality Guidelines for Europe (in press). 8

9 Dichloroethane Dichloroethane has had limited use as an additive to leaded gasoline and as an industrial solvent, but we evaluated it because of its production and use for PVC manufactoring at a petrochemical plant in Sweden. It is not expected to be a general air pollutant. It is classified by the IARC in Group 2B (possibly carcinogenic to humans). Our document on dichloroethane is from 1986, which means that many studies should have been published since then, although we have not updated the literature. At that time mutagenic effects had been demonstrated in vitro. There were two cancer studies with rats and mice - one positive showing different tumour forms after administration via gavage and one negative inhalation study. As there were indications that detoxification mechanisms were exceeded in the oral study but not in the inhalation study, we preferred to use an uncertainty factor approach rather than extrapolation models. The NOEL for cancer and irreversible liver and kidney damage, ppm, divided by an uncertainty factor of 1000 gave a low risk level of ppb ( µg/m 3 ). In contrast, the EPA (IRIS database) presents a unit risk estimate (2, per µg/m 3 ) that is based on risk extrapolation using the multistage model on the results of the oral cancer study, recalculated for inhalation by assuming 100% absorption and metabolism. According to this risk estimate, a lifetime cancer risk of would be equivalent to 0.1 ppb - a 1000-fold lower value. 9

10 Dichloromethane (Methylene Chloride) Dichloromethane is used internationally as an industrial solvent for degreasing and paint removal etc, but in Sweden its use is now severely restricted. It is classified by the IARC in Group 2B (possibly carcinogenic to humans). Inhalation studies have shown an increased incidence of lung and liver tumours in mice and benign mammary tumours in rats, but no tumours in syrian hamsters. Dichloromethane is mutagenic to bacteria, but in cell cultures it has either given negative or weak positive results concerning mutations. It has induced chromosomal aberrations, but not sister chromatid exchanges, in vitro. At the time of our review, there were mainly negative results from in vivo genotoxicity testing, but later studies have indicated DNA damage in mice. In the IMM health risk assessment of dichloromethane in 1990, we used an uncertainty factor approach rather than a cancer risk extrapolation model, despite demonstrated genotoxic effects. The reason for this was internationally ongoing efforts to try to incorporate toxicokinetic data into the model, and that different such models yield different risks at low concentrations. While awaiting further results from the validation of pharmacokinetic models, the risk assessment was conducted by applying an uncertainty factor of 5000 to the LOEL for carcinogenic effects in inhalation studies, 500 ppm, thus resulting in a low-risk level of 100 ppb (350 µg/m 3 ). The risk assessment of dichloromethane will be updated at IMM during For dichloromethane the EPA (IRIS database) has calculated a unit risk ( per µg/m 3 ) based on combined liver and lung tumours in mice with incorporated information on pharmacokinetics and metabolism. According to this risk estimate, a lifetime cancer risk of would be equivalent to 6 ppb (20 µg/m 3 ). In the WHO Air Quality Guidelines for Europe, 3000 µg/m 3 as a 24 h mean is recommended, which would cause a 0.1% increase in carboxyhemoglobin (COHb) formation in humans. 10

11 Ethene Ethene is produced and used in petrochemical industries, but it is also a common air pollutant from e.g. vehicle exhausts. According to the IARC, it is not classifiable as to its carcinogenicity to humans (Group 3). There is a negative inhalation study with rats, and ethene is not mutagenic in the Ames test. However, ethene is metabolised to ethylene oxide, which is clearly genotoxic and carcinogenic (see below). As the metabolism of ethene to ethylene oxide is saturable, no more than concentrations equivalent to inhalation of approximately 4-8 ppm of ethylene oxide will be formed. This formation is too low to be expected to result in a statistically significant increased cancer incidence. However, in our opinion this does not mean that the cancer risk at low inhalation doses should be neglected. According to investigations by Törnqvist and Ehrenberg, the mean degree of metabolism was assumed to be 5%. The EPA unit risk for ethylene oxide was then used to give a low-risk level of 1 ppb, equivalent to an increased life-time cancer risk of Törnqvist and Ehrenberg have developed an alternative risk assessment of ethene based on their so-called rad-equivalence method, that leads to a 10-fold higher risk for all types of cancer. 11

12 Ethylene oxide Ethylene oxide is an important petrochemical product and intermediate, and was evaluated by the IMM because some ethylene oxide is emitted from a petrochemical complex in Sweden. It is not regarded as a general air pollutant. Ethylene oxide is an alkylating agent that binds to DNA and is genotoxic in several test systems both in vitro and in vivo. It has also caused DNA damage in male germ cells, as well as hereditary mutations and translocations. Several epidemiological studies on ethylene oxide-exposed workers have shown different genotoxic effects in lymphocytes, such as chromosome aberrations, sister chromatid exchanges, micronuclei and even point mutations. Ethylene oxide is classified by the IARC as a human carcinogen (Group 1). The epidemiological studies were classified as of limited evidence, but the animal studies as sufficient. Several epidemiological studies have shown an increased risk for leukemia or other lymphatic and haematopoietic cancer in occupationally-exposed workers. Two different inhalation studies with rats showed most notably an increased incidence of leukemia and brain tumours, and two inhalation studies with mice showed an increase in lung tumours (among other tumour forms). Ethylene oxide is not included in the EPA IRIS database. However, in an EPA report on ethylene oxide from 1985, risk estimates were calculated using the standard multistage model based on leukemia and brain tumours in female rats from one of the rat studies (the most sensitive one). According to this estimate, a lifetime cancer risk of would occur from inhalation of 0.05 ppb of ethylene oxide. Other risk estimates from the rat studies have yielded somewhat lower risks, but in our updated evaluation from 1992 we still recommend the low-risk level of 0.05 ppb. The rad-equivalence approach of Ehrenberg and Törnqvist resulted in a 10-fold higher risk for all cancer types. 12

13 Formaldehyde Formaldehyde is a widely used chemical. The most important sources of formaldehyde in ambient air are engine exhaust and the photochemical oxidation of hydrocarbons, released from combustion processes and other sources. Formaldehyde is classified by IARC in Group 2A (probably carcinogenic to humans). Inhalation of formaldehyde causes nasal cancer in rats and probably also in mice, but not in hamsters. It also causes cell proliferation and tissue damage in the nasal mucosa, and these effects are considered to contribute to the subsequent development of cancer. Taken together, epidemiological studies suggest a causal relationship between exposure to formaldehyde and nasopharyngeal cancer. Formaldehyde is genotoxic in several experimental systems, both in vitro and in vivo. Our risk assessment dates back to 1983, but we would probably come to a similar conclusion today in spite of many additional animal and human studies. Our recommended guideline value was based on the irritative properties of formaldehyde. An uncertainty factor of 10, applied to ppm, where irritation to the eyes and upper airways may occur in sensitive individuals, led to a recommended guideline value of ppb (12-60 µg/m 3 ). We regarded this dose range as a low-risk level, even when considering cancer effects. The reason for this was that the cytotoxicity of formaldehyde probably is a prerequisite for nasal tumours, and that the dose-response curve for tumours was very steep. The WHO has drawn similar conclusions in the updated Air Quality Guidelines for Europe (in press), and recommends 100 µg/m 3 as a 30-min average. In contrast, the EPA presents a unit risk estimate in the IRIS database that for a lifetime cancer risk of would correspond to 0.8 µg/m 3. 13

14 2-Nitropropane The main use of nitropropane is as an extraction solvent for organic material and as a chemical intermediate. It is not a common air pollutant, but was evaluated by the IMM mainly because of its use in industry. Nitropropane is genotoxic in several in vitro test systems and has caused liver cancer in rats in a subchronic inhalation study. In a chronic inhalation study with lower concentrations, only preneoplastic liver nodules were demonstrated. Nitropropane has also caused other hepatotoxic effects, and was considered to cause cancer by a combination of genotoxic and nongenotoxic mechanisms. Extrapolation of cancer data in the subchronic study or of the nodules in the chronic study both led to a low-risk level of 2 ppb (multistage modelling, no species conversion factor). However, the toxicological data that formed the basis for these extrapolations were less sufficient. An uncertainty factor approach led to 5 ppb, based on a NOEL of 25 ppm for liver cancer and an uncertainty factor of The EPA (IRIS database) also recommends 5 ppb (20 µg/m 3 ), based on a time-adjusted LOEL of 25 ppm concerning liver nodules in the chronic study and an uncertainty factor of Nitropropane is classified by the IARC in Group 2B (possibly carcinogenic to humans). 14

15 Propene Propene is produced in petroleum refining and cracking processes, and is used as a chemical intermediate. It is also formed in combustion processes, and is a general air pollutant. There is a negative inhalation cancer study with propene, but in the body propene is metabolised to propylene oxide that has given rise to nasal tumours and other tumour forms in rats and mice after inhalation. However, these cancer studies are less well-suited for quantitative risk extrapolations although there is a unit risk estimate from the EPA. The degree of metabolism of propene to propylene oxide in humans is not known, but in mice it is approximately 10%. If the EPA unit risk were used, it would lead to a low risk level of 10 ppb, assuming a 10% metabolism rate. Data from Ehrenberg and Törnqvist on comparative genotoxicity and haemoglobin adducts relative to ethene would lead to 0.7 ppb using the rad-equivalence method and 3.5 ppb using the EPA unit risk factor for ethylene oxide. We recommended 10 ppb, but as these risk assessments are all very uncertain, we also used an uncertainty factor of 5000 applied to the lowest concentration of propylene oxide that gave an increased tumour incidence in rats, 100 ppb, which would lead to a low risk level of 20 ppb for propylene oxide, equivalent to 200 ppb for propene. Propene oxide, but not propene, is genotoxic in vitro. According to the IARC, propene is not classifiable as to its carcinogenicity to humans (Group 3). It is not included in the WHO Air Quality Guidelines. 15

16 Styrene Styrene is widely used as a monomer for the production of plastics, synthetic rubber, glass fibre-reinforced polyester products, etc. It can be a local air pollutant around such facilities, but some styrene is also found in automobile exhaust. Although our risk assessment on styrene dates back to 1984, no new animal cancer studies have been published, and there is still no good, long-term inhalation study. From the available studies, there is no convincing evidence of carcinogenic activity in laboratory animals. The metabolite styrene-7,8- oxide is shown to be carcinogenic, mainly to the forestomach of rats and mice after gavage exposure. There have been many more epidemiological studies on styrene-exposed workers since Taken together, several of these epidemiological studies have shown that workers exposed to styrene in the reinforced plastics industry have increased risks of lymphatic and hematopoietic tumours. The studies are not, however, fully conclusive. The IARC has classified styrene in Group 2B (possibly carcinogenic to humans). Styrene has been mainly negative in bacterial genotoxicity/mutagenicity tests, but chromosomal damage occurred in human lymphocytes in vitro and in some other assays that allow effective metabolic activation. In vivo data have given conflicting results, but DNA- and protein adducts as well as a weak induction of sister chromatid exchanges and DNA single strand breaks have been demonstrated in vivo. The reactive styrene metabolite, styrene-7,8-oxide is genotoxic in several in vitro test systems, and has also induced chromosomal damage in mice in vivo. Several studies have demonstrated chromosomal damage in the lymphocytes of styrene-exposed workers. As quantitative risk assessments could not be performed based on cancer data, our risk assessment was based on the chromosomal effects in humans. We indicated a LOEL at ppm which, divided by an uncertainty factor of , would lead to a low-risk level of ppb ( µg/m 3 ). We recommended the lower value. It should be noticed, however, that styrene has a very low odour threshold (50-80 ppb according to our document, 16 ppb according to the WHO Air Quality Guidelines). Thus, in practice, the odorous properties of styrene may well be the limiting factor when discussing allowable emissions from individual industries. 16

17 In the updated WHO Air Quality Guidelines for Europe, the recommended value is instead based on neurotoxic effects. Subtle effects, such as decreased verbal learning skills and subclinical effects on colour vision, have been observed in occupationally-exposed populations at ppm, which divided by an uncertainty factor lead to a guideline of 60 ppb (260 µg/m 3 ). The recommended value from the EPA (IRIS database) is higher, 235 ppb (1000 µg/m 3 ), but is also based on neurotoxic effects in workers. 17

18 Tetrachloroethylene Tetrachloroethylene is a chlorinated solvent, that is used internationally for dry cleaning, metal cleaning, etc. and as a chemical intermediate. In Sweden it is prohibited in consumer products, but it is still used for dry cleaning textiles. It is a widespread environmental pollutant. Inhalation of tetrachloroethylene has caused liver cancer in mice and leukemia in rats along with a marginal increase in renal tumours in male rats. It is mainly non-genotoxic in vitro and in vivo. Peroxisome proliferation has been discussed as a possible epigenetic mechanism for the liver tumours. It is classified by IARC in Group 2A (probably carcinogenic to humans). The risk assessment from the IMM was based on the LOEL for carcinogenic effects in mice and rats, 200 ppm. Divided by an uncertainty factor of , this would lead to a low-risk level in the range ppb with a recommended value of 100 ppb (680 µg/m 3 ). In the updated WHO Air Quality Guidelines for Europe, the risk assessment is instead based on the increased incidence of renal damage that has been demonstrated in dry cleaning workers. The LOEL for this effect was set at 15 ppm, which divided by an uncertainty factor, led to a recommended value of 37 ppb (250 µg/m 3 ). Tetrachlorethylene is not included in the EPA IRIS database in terms of inhalation exposure. 18

19 Trichloroethylene Internationally, trichloroethylene is mainly used for metal cleaning and degreasing, but in Sweden its use is now severely restricted. In inhalation experiments an increased incidence of mainly liver and lung tumours has been demonstrated in mice, and testicular tumours and a marginal increase in renal tumours in rats. At the time of our review, the results on genotoxic effects were equivocal or low both in vitro and in vivo, and epigenetic mechanisms were thought to probably contribute to the observed cancer effects. There are now more recent studies that suggest a genotoxic potential of trichloroethylene. The IARC has classified trichloroethylene in Group 2A (probably carcinogenic to humans). In the risk assessment from the IMM, trichloroethylene was regarded as essentially non-genotoxic, and consequently a LOEL/uncertainty factor approach was used. The LOEL was 100 ppm for cancer, and an uncertainty factor of gave a low-risk level of ppb ( µg/m 3 ). In contrast, the weak genotoxic effects led the WHO to apply an extrapolation model in their updated Air quality guidelines for Europe. The multistage model was applied to lung tumours in mice and testicular tumours in rats. The latter gave the highest unit risk, which for a lifetime risk of would correspond to 4.3 ppb (23 µg/m 3 ). With regard to the new data on genotoxicity, the IMM would most probably also use a non-threshold approach for risk assessment of trichloroethylene if we were to revise our document. Trichlorethene is not included in the EPA IRIS database considering inhalation exposure. 19

20 Vinyl chloride Vinyl chloride is mainly used for the production of polyvinylchloride (PVCplastics), and may be released into ambient air during its production or its use for this purpose. Several epidemiological studies have shown a causal association between vinyl chloride and angiosarcoma of the liver among other tumour forms. In experimental animals different tumour forms have been induced, such as mammary tumours and angiosarcomas of the liver. It is genotoxic in several test systems both in vitro and in vivo and in humans. It is classified by the IARC as carcinogenic to humans (Group 1). For the quantitative risk assessment, the IMM referred to older mathematical modelling of the rat inhalation data. The one chosen was based on the incidence of angiosarcomas in the liver and gave a risk that transformed to continouos exposure without species conversion would lead to a lifetime risk of at 1.7 ppb (4.4 µg/m 3 ). However, mammary tumours appeared at 10-fold lower concentrations than angiosarcomas, and an uncertainty factor of 5000 applied to the LOEL (5 ppm) would lead to a lower low-risk level, 1 ppb (2.6 µg/m 3 ). As vinyl chloride is not a general air pollutant, it is not included in the WHO Air Quality Guidelines for Europe. Vinyl chloride is not included in the EPA IRIS database. 20

21 Acknowledgements This updated summary has been reviewed by Drs. Siv Ljungquist and Sten Flodström. References Ahlborg UG, Flodström S, Ljungquist S, Neelakantan L, Rondahl L och Wärngård L. Medicinska och hygieniska effekter av formaldehyd. Litteraturgenomgång och toxikologisk utvärdering (Health risk assessment of formaldehyde). Rapport SNV PM Naturvårdsverket, 1983 (In Swedish) Ahlborg UG, Flodström S, Ljungquist S, Rondahl L och Wärngård L. Medicinska och hygieniska effekter av styren i omgivningsluft. Litteraturgenomgång och toxikologisk utvärdering (Health risk assessment of styrene). Rapport SNV PM Naturvårdsverket, 1984 (In Swedish) EPA. Integrated risk information service (IRIS). US EPA database, on-line. Fransson R, Ahlborg A. Medicinska och hygieniska effekter av diklormetan, trikloreten och tetrakloreten i omgivningsluft (Health risk assessment of dichloromethane, trichloroethylene and tetrachloroethylene). IMM-rapport 5/90. Institutet för miljömedicin, (In Swedish with English summary). Fransson-Steen R, Ljungquist S, Victorin K. Uppdaterad hälsoriskbedömning av bensen (Updated health risk assessment of benzene). IMM-rapport 3/94. Institutet för miljömedicin, (In Swedish with English summary) IARC Monographs on the evaluation of carcinogenic risks to humans, Supplement 7. IARC, 1987 (benzene, dichloroethane, dichloromethane, 2-nitropropane, vinyl chloride) IARC Monographs on the evaluation of carcinogenic risks to humans, Volumes 54 (butadiene), 60 (ethylene, ethylene oxide, propylene, styrene), 62 (formaldehyde) and 63 (trichloroethylene, tetrachloroethylene). IARC 1992, 1994 and

22 Kenne K, Ljungquist S. Medicinska och hygieniska effekter av 2-nitropropan i omgivningsluft (Health risk evaluation of 2-nitropropane). IMM-rapport 4/91. Institutet för miljömedicin, (In Swedish) Ljungquist S och Ahlborg UG. Medicinska och hygieniska effekter av butadien i omgivningsluft. Litteraturgenomgång och toxikologisk utvärdering. Rapport till MUST (Miljöutredningen för Stenungsund) (Health risk assessment of butadiene). SNV Rapport nr Naturvårdsverket, 1986 (In Swedish) Rondahl L, Victorin K, Ljungquist S, Ahlborg UG. Medicinska och hygieniska effekter av dikloretan i omgivningsluft. Litteraturgenomgång och toxikologisk utvärdering (Literature survey and toxicological evaluation of dichloroethane). Rapport till MUST (Miljöutredningen för Stenungsund). SNV Rapport Naturvårdsverket, (In Swedish) Törnqvist M, Ehrenberg L. On cancer risk estimation of urban air pollution. Environ Health Perspect 102, suppl 4, , Victorin K, Pettersson B, Ahlborg UG. Medicinska och hygieniska effekter av vinylklorid i omgivningsluft. Litteraturgenomgång och toxikologisk utvärdering (Literature survey and toxicological evaluation of vinyl chloride). Rapport till MUST (Miljöutredningen för Stenungsund). SNV Rapport Naturvårdsverket, (In Swedish) Victorin K. Uppdaterad hälsoriskbedömning av etenoxid, eten och propen (Revised health risk assessment of ethylene oxide, ethene and propene). IMM-rapport 8/92. Institutet för miljömedicin, (In Swedish with English summary) WHO. Air Quality Guidelines for Europe. WHO, Updated and revised version in press.

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