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Carcinogenicity

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Description of key information

Several studies have been conducted in rodents which appear to be very insensitive models for carciinogenicity. Epidemiology studies in human have consistently demonstrated that human exposure to inorganic arsenic lead to an increase incidence in cancer in several organs mainly skin, bladder and lungs.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Dose descriptor:
NOAEL
1.7 µg/kg bw/day

Carcinogenicity: via inhalation route

Endpoint conclusion
Dose descriptor:
NOAEC
6 µg/m³

Carcinogenicity: via dermal route

Endpoint conclusion
Dose descriptor:
NOAEL
85 µg/kg bw/day

Additional information

Most studies of animals exposed to arsenate or even arsenite expected to be more toxic, have not detected any clear evidence for an increased incidence of skin cancer or other cancers (Byron et al. 1967; Kroes et al. 1974; Schroeder et al. 1968). The basis for the lack of tumorigenicity in animals is not known, but could be related to species-specific differences in arsenic distribution, and induction of cell proliferation. Most of these studies are old, of limited quality and do not bring relevant information. However, although it was conducted on sodium arsenite, we reported a study conducted by Waalkes et al (2004, 2007). In this study pregnant C3H mice were received sodium arsenite in drinking water at 0 (control), 42.5, and 85 ppm arsenite ad libitum from day 8 to 18 of gestation. After gestation day 18 there was no further arsenic treatment and Dams were allowed to give birth. In male offspring exposed to arsenic in utero developed liver carcinoma and adrenal cortical adenoma in a dose-related manner. In female offspring, a dose-related increase in ovarian tumors, lung carcinoma and proliferative lesions of the uterus and oviduct was observed.

 However, there is convincing evidence from a large number of epidemiological studies and case reports that ingestion or inhalation of inorganic arsenic increases the risk of developing skin bladder, kidney, liver and lung cancer. A selection of these studies has been reported there. Selection was mainly based on study quality and the possibility to define a reliable dose effect relationship.

 

For inhalation exposure, most studies involved workers exposed primarily to arsenic trioxide dust in air at copper smelters and despite some good studies with some information on dose effect relationship, these studies have many shortcomings and do not allow the definition of a reliable NOAEL for arsenic acid to derive a relevant DNEL. The more reliable is a study by Jarup et al, (1989) in which the cause-specific mortality was followed through 1981 in a cohort of 3,916 male Swedish smelter workers employed for at least 3 months from 1928 through 1967. Arsenic levels in the air of all workplaces within the smelter were estimated for three different time periods. Using this exposure matrix and detailed information of the work history, cumulative arsenic exposure could be computed for each worker. Standardized mortality ratios (SMRs) were calculated for several dose categories using age-specific mortality rates from the county where the smelter was situated. A positive dose-response relationship was found between cumulative arsenic exposure and lung cancer mortality with an overall SMR of 372 (304-450, 95% confidence interval). The lung cancer mortality was related to the estimated average intensity of exposure to arsenic but not to the duration. SMR’s ranged from 271 (<0.25 mg year/m3) to 1137 (<100 mg*year/m3). However, smoking pattern was not recorded in this study and there was some indication that it was different from the reference population. This may explain the lack of dose response until 50 mg*years/m3in this study..

 

A number of epidemiological studies deal with oral absorptionespecially with the carcinogenic effects of excessive amount of inorganic arsenic in drinking water. The three main cancer types which have been identified in these studies and for which NOAEL can be derived from epidemiological studies are skin, bladder and lungs.

 

Carcinogenic effect of arsenic to skin is well known. It have been reviewed recently by Yu et al (2006). The most common arsenic-induced skin cancers are Bowen's disease (carcinoma in situ), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Arsenic-induced Bowen's disease (As-BD) is able to transform into invasive BCC and SCC. Individuals with As-BD are considered for more aggressive cancer screening in the lung and urinary bladder. However, Beane et al (2004) also described an increased incidence of skin melanoma in correlation with increased intake of inorganic arsenic in drinking water. As this finding has not been confirmed so far, it has to be considered with caution. Specific skin lesions will often appear before the cancer lesions and they also have been well studied with a good correlation with dietary exposure (Ashan et al, 2006) in Bangladesh. In this study the authors evaluated dose-response relations between arsenic exposure from drinking water and premalignant skin lesions by using baseline data on 11,746 participants recruited in 2000-2002.

 

Bladder cancer incidence has been studied by Chiou (2001). In this study the authors examined risk of transitional cell carcinoma (TCC) in relation to ingested arsenic in a cohort of 8102 residents in north-eastern Taiwan. Estimation of each study subject's individual exposure to inorganic arsenic was based on the arsenic concentration in his or her own well water. Information on duration of consumption of the well water was obtained through standardized questionnaire interviews. The occurrence of urinary tract cancers was ascertained by follow-up interview and by data linkage with community hospital records, the national death certification profile, and the cancer registry profile. Two other publications report on dose effect relationship for bladder cancer: Guo et al (2000) and Bates et al (2004). Guo et al (2000) is a village based ecological study conducted in Taiwan using cancer registry and death certificates; there is no increased incidence of bladder cancer below an Arsenic water concentration of 0.64 mg/L. The next lowest dose without effect is the group with water concentration between 0.33 and 0.64 mg/L. Bates et al (2004) is a case control study conducted in Argentina. Cases were recruited in different clinics of the area and exposure was assessed by measurement of the Arsenic concentration of their residence. There found no increased incidence of bladder cancer with an Arsenic water concentration up to 200 mg/L (group between 200 and 389 µg/L). There was a potential increase in subject who ever smoked and were exposed more that 50 years to arsenic but the significance of that is unclear.

 

Lung cancer incidence has been studied by Buchet et al (1998). A cohort study was conducted to analyse the statistics of mortality in Belgian population previously exposed to As from natural (drinking water) and/or industrial (nonferrous metal smelter emissions) sources. Mortality data and underlying causes were obtained from the Belgian National Institute of Statistics. A moderately increased absorption of As, leading to a 3- to 4- fold higher urinary excretion (35 µg/day as compared with 6-10 µg As/day in nonexposed subjects) did not enhance the mortality by diseases of the nervous system, liver and heart, and cancers. An increase in mortality by lung cancer, however, was observed in men but not women living around zinc smelters but might be related to past occupational exposure and/or smoking habits. In conclusion, a low to moderate level of environmental exposure to inorganic arsenic does not seem to affect the causes of mortality, suggesting in particular nonlinearity of the dose-response relationship for arsenic and cancer. Ferreccio et al (2000) conducted a case-control study to assess the relation between lung cancer and arsenic in drinking water in northern Chile. Study identified 152 lung cancer cases (1994-1996) and 419 frequency-matched hospital controls. Information on drinking water sources, cigarette smoking, and other variable was obtained through standardized questionnaire interviews. Logistic regression analysis revealed a clear trend in lung cancer odds ratios and 95% confidence intervals (CIs) with increasing concentration of arsenic in drinking water. There was evidence of synergy between cigarette smoking and ingestion of arsenic in drinking water; the odds ratio for lung cancer was 32.0 (95% CI = 7.2-198.0) among smokers exposed to more than 200 µg/L of arsenic in drinking water (lifetime average) compared with non-smokers exposed to less than 50 µg/L. Under the conditions of the study, an association was found between ingestion of inorganic arsenic at more than 75 µg/L and risk of human lung cancer.

 

In conclusion, despite limited evidence from animal studies, inorganic arsenic, including pentavalent form (and then arsenic acid) can be considered as a proven human carcinogen. There is still considerable controversy on the exact mechanism and the existence or not of a threshold, although there is some in vitro positive mutagenicity studies. As arsenic is a naturally occurring substance with an unavoidable background exposure for the general population, a threshold approach can be favoured for risk assessment. 

 

 

Justification for classification or non-classification

Epidemiology studies in human have consistently demonstrated that human exposure to inorganic arsenic lead to an increase incidence in cancer in several organs mainly skin, bladder and lungs. In consequence, arsenic acid should be classified as Carc. 1A – H350 according to CLP.