Executive summary. Scope

Transcription

1 Executive summary Scope At the request of the Minister of Social Affairs and Employment, the Health Council of the Netherlands sets Health-Based Calculated Occupational Cancer Risk Values (HBC-OCRVs) for chemical substances in air at the workplace. These recommendations are made by the Council s Dutch Expert Committee on Occupational Safety (DECOS). These recommendations serve as a basis in setting legally binding occupational exposure limits by the Minister. In this report, the Committee discusses the consequences of occupational exposure to arsenic and arsenic compounds and presents HBC-OCRVs associated with excess mortality levels of 4 per 1,000 and 4 per 100,000 as a result of working life exposure. The Committee s conclusions are based on scientific papers published prior to September 3, Physical and chemical properties Arsenic (As; CAS no ) is a naturally occurring grey, crystalline solid with metallic luster and has a molecular weight of Elemental arsenic sublimes at 613 C, has a very low vapour pressure and a log P octanol/water of Arsenic compounds, crystalline, amorphous or hygroscopic substances, occur in trivalent and pentavalent forms. Arsenic trioxide (CAS no ), the major arsenic compound with regard to occupational exposure, has a molecular weight Executive summary 17

2 of , melts at 312 C, boils at 465 C, has also a very low vapour pressure and a log P octanol/water of Use Arsenic and/or arsenic compounds are used as wood preservative, in agriculture (mainly in the past), as a cotton desiccant/defoliant, in a variety of semiconductor applications, as a decolouriser and fining agent in the production of bottle glass and other glassware, in the production of non-ferrous alloys and as a medication. Monitoring Arsenic and arsenic compounds in air are usually associated with particulate matter and therefore standard methods of the National Institute for Occupational Safety and Health (NIOSH) and the Occupational Safety and Health Administration (OSHA) involve collection of air samples on glass fibre or membrane filters, acid extraction of the filters (digestion with nitric, sulphuric and/or perchloric acids) and arsine generation. Hydride generation atomic absorption spectrometry and graphite furnace atomic absorption spectrometry are the major analysis techniques (NIOSH method 5022 (particulate organoarsenicals), NIOSH method 7900 (arsenic and compounds as As, except AsH 3 and As 2 O 3 ), NIOSH method 7901 (arsenic trioxide, as As) and OSHA method ID-105 (arsenic)). Furthermore, inductively-coupled argon plasma, atomic emission spectroscopy is used to analyse arsenic (NIOSH method 7300 (arsenic)). Although different methods for biological monitoring are available, none of these methods is validated. Guidelines Currently, the legal time weighted average (TWA) (8 hr) and short-term (15 min) occupational exposure limits for the combination of all inorganic arsenic compounds in the Netherlands are 0.05 and 0.1 mg As/m 3, respectively. The legal TWA (8 hr) and short-term (15 min) occupational exposure limits for the watersoluble inorganic arsenic compounds are and 0.05 mg As/m 3, respectively. There is currently no limit value for exposure to arsenic and arsenic compounds at the European level. In Germany, an 8 hr TRK (Technische Richtkonzentration) and a short time (15 min) TRK of 0.1 mg/m 3 and 0.4 mg/m 3 are established, respectively. The United Kingdom, Denmark and Sweden have 18 Arsenic and inorganic arsenic compounds

3 set an occupational exposure limit (8 hr TWA value) for arsenic and compounds (as As) of 0.1 mg/m 3, 0.01 mg/m 3 and 0.03 mg/m 3, respectively. The American Conference of Governmental Industrial Hygienists (ACGIH) has specified a threshold limit value (TLV) of 0.01 mg/m 3 (as As) (8 hr TWA value). The permissible exposure limit (PEL) for inorganic arsenic of the Occupational Safety and Health Administration (OSHA) is 10 µg/m 3. Furthermore, the recommended standard of NIOSH amounts to mg/m 3 as determined by a 15-minute sampling period (inorganic compounds, as As). Kinetics and mechanism of action Both pentavalent and trivalent soluble arsenic compounds are rapidly and extensively absorbed from the gastrointestinal tract. Absorption of arsenic from inhaled airborne particles is highly dependent on the solubility and the size of particles. Dermal absorption appears to be much less than absorption by the oral or inhalation routes. Arsenic and its metabolites distribute to all organs in the body; preferential distribution has not been observed. Arsenic readily crosses the placenta. Arsenic metabolism is characterised by alternation of two main types of reactions: (1) two-electron reduction reactions of pentavalent to trivalent arsenic and (2) oxidative methylation reactions in which trivalent forms of arsenic are converted to (mono-, di- or tri-) methylated pentavalent products. Arsenic and its metabolites are largely excreted via the renal route. Excretion can also occur via faeces; minor excretion pathway are nails and hair. Different studies indicated that arsenic can be excreted in human milk. Trivalent (in)organic arsenic reacts strongly with sulfhydryl groups in proteins and inactivates many enzymes. A particular target in the cell is the mitochondria. Pentavalent inorganic arsenic may exert effects by acting as a phosphate analogue and could potentially affect a number of biological processes, including ATP production, bone formation, and DNA synthesis (uncoupling of oxidative phosphorylation). Effects Human toxicity data Relatively little information is available on the local effects of arsenic and arsenic compounds. Arsenic trioxide is a corrosive compound and may cause local damage to the skin, eyes and respiratory tract. Executive summary 19

4 No cases were located regarding death in humans from inhalation exposure to inorganic arsenicals following acute exposure, even at the very high exposure levels (1-100 mg As/m 3 ) found previously in the workplace. Acute ingestion of large doses of arsenic leads to gastrointestinal symptoms, disturbances of cardiovascular and nervous system functions, and eventually death. In survivors, bone marrow depression, haemolysis, hepatomegaly, melanosis, polyneuropathy and encephalopathy may be observed. Arsenic is considered to be a non-stochastic genotoxic compound. Clastogenic damage was observed in different cell types of exposed humans and in mammalian cells in vitro. For point mutations, the results are largely negative. With regard to the mechanism which caused the genotoxic effects, there is evidence that DNA repair enzymes are inhibited by arsenicals, that DNA is hypo- or hypermethylated and that oxidative damage by reactive oxygen species plays a role in arsenic genotoxicity. Long-term exposure to arsenic in drinking-water is causally related to increased risks of cancer in the skin, liver, lungs, bladder and kidney, as well as other skin changes such as hyperkeratosis and pigmentation changes. The effects have been most thoroughly studied in Taiwan but there is considerable evidence from studies on populations in other countries as well. Increased risks of lung and bladder cancer and of arsenic-associated skin lesions have been reported to be associated with arsenic exposure categories of 50 µg/l. Chronic oral (drinking water) arsenic exposure in Taiwan may be associated with blackfoot disease, a severe form of peripheral vascular disease which leads to gangrenous changes. There is good evidence from studies in several countries that arsenic exposure causes other forms of peripheral vascular disease. Conclusions on the causality of the relationship between oral arsenic exposure and other health effects (hypertension, cardiovascular disease, diabetes, cerebrovascular disease, long-term neurological effects) are less clear-cut. Occupational exposure to arsenic by inhalation is causally associated with lung cancer. Exposure-response relationships and high risks have been observed. Increased risks have been observed at relatively low cumulative exposure levels in smelter cohorts in Sweden (Rönnskär; arsenic exposure category of < 250 µg/ m 3 year) and in the USA (Tacoma; arsenic exposure category of < 750 µg/ m 3 year). Studies indicated that smoking had a synergistic effect on the lung cancer effects of arsenic exposure. Several studies have examined a number of reproductive end-points in relation to arsenic exposure. Occupational exposure studies are not conclusive on a causal relationship between arsenic and reprotoxic effects. Studies on oral exposure to arsenic in drinking water show that arsenic can not be excluded as a 20 Arsenic and inorganic arsenic compounds

5 causal factor for reproduction toxicity (spontaneous abortion, neonatal and postnatal mortality, preterm delivery, reduced birth weight) (see Annex K). Effects Animal toxicity data Relatively little information is available on the local effects of arsenic and arsenic compounds in animals. Sodium arsenite and sodium arsenate were not allergenic in the guinea-pig maximisation test. In a developmental toxicity study, 100% mortality in groups of 10 pregnant rats after 1 day of inhalation exposure to arsenic trioxide concentrations 100 mg/m 3 was observed (76 mg As/m 3 ). The acute dermal LD 50 for the pentavalent arsenicals calcium arsenate and lead arsenate in the rat is 2400 mg/kg bw ( 400 mg As/kg bw). Oral and parenteral lethal doses range from 15 to 960 mg As/kg bw/day, depending on the compound and the animal species. Arsenic produced chromosomal aberrations in vivo and in vitro Several animal carcinogenicity studies on arsenic have been carried out, but limitations such as limited time of exposure and limited number of animals make these inconclusive. In a recent study, female C57B1/6J mice had an increased incidence in tumours involving mainly lung, liver, gastrointestinal tract and skin after exposure to 500 µg As V /L * drinking water for 2 years. One study has indicated that dimethylarsinic acid may cause cancer of the urinary bladder in male rats at high doses. Studies with mice, rats and hamsters revealed that inorganic arsenic caused reprotoxic effects (reduced birth weight, foetal malformations, increased foetal mortality) upon inhalatory, oral and parenteral administration of relatively high arsenic doses which were usually maternally toxic (and often nearly fatal). Reproductive performance was not affected in female rats that received inhalation exposures to concentrations as high as 20 mg As/m 3 or gavage doses as high as 8 mg As/kg bw/day from 14 days prior to mating through gestation day 19. Little information is available with regard to immunological effects of arsenic and arsenic compounds in animals. * pentavalent arsenic (As v ) versus trivalent arsenic (As III ) Executive summary 21

6 Evaluation and advice Arsenic and arsenic compounds are considered to be carcinogenic in humans (classification category 1A, see Annex I and J). Because sufficient adequate human data on arsenic and arsenic compounds are available the available human data are used for derivation of the occupational limit value. Lung cancer is the critical effect after inhalation exposure to arsenic and arsenic compounds. Sufficient quantitative information from human studies on the levels of arsenic exposure to ensure reliable assessment of the exposureresponse relationship was available for three copper smelter cohorts: Tacoma, Washington (USA), Anaconda, Montana (USA) and Rönnskär (Sweden). Arsenic and inorganic arsenic compounds have non-stochastic genotoxic mechanisms (see Annex I). For quantitative hazard assessment the Committee decided not to pursue a threshold approach but to calculate excess lifetime cancer mortality risks (health-based calculated occupational cancer risk values (HBC- OCRV)), using mathematical modeling and extrapolation. The Committee compared the quality and suitability for quantitative hazard assessment of four epidemiological studies on lung and respiratory cancer mortality among workers in these smelters (Lubin et al , , Järup et al and Enterline et al ) and selects the study of Lubin et al. (2000) 1 for the derivation of HBC-OCRV using a linear model. The Committee calculates that the concentration of arsenic in the air, which corresponds to an excess cancer mortality of 4 per 1,000 (4x10-3 ), for 40 years of occupational exposure, equals to 28 µg/m 3 4 per 100,000 (4x10-5 ), for 40 years of occupational exposure, equals to 0.28 µg/m 3. The available data do not warrant the setting of a Short Term Exposure Limit (STEL) or ceiling value. The rate of absorption of arsenic and arsenic compounds through the skin does not warrant a skin notation. 22 Arsenic and inorganic arsenic compounds