Nickel and its Compounds - PSL1

3.0 Assessment of "Toxic" under CEPA

3.1 CEPA 11(a) Environment

Nickel is a naturally occurring element that is present in the environment principally in the divalent state. Annual production and imports of nickel in 1990 were 197 000 t and 29 000 t, respectively, of which 187 000 t were exported. Metallic nickel, nickel alloys, and various nickel compounds are widely used in the transportation, electrical, chemical, and other industrial sectors.

Nickel (in various, mainly inorganic forms) enters the atmospheric, aquatic, and terrestrial (soil) environment naturally, and as a result of anthropogenic activities. Natural sources of nickel include the weathering and erosion of bedrock (particularly nickel-enriched ultramafic or sulphide-bearing types), and at one location (Smoking Hills, NWT), the spontaneous combustion of nickel-bearing bituminous shales. As a result, concentrations of nickel are naturally elevated (relative to normal background values) in soils and surface waters in some parts of Canada.

Anthropogenic sources, which release nickel in both dissolved and particulate forms to Canadian surface waters, include mining and milling of nickel, gold and uranium ores, and iron and steel processing. The main anthropogenic sources of nickel released into the Canadian atmosphere are nickel smelting and refining operations (Sudbury, Ontario and Thompson, Manitoba), and to a lesser extent, fossil fuel combustion. Based on examination of flue dusts, nickel released from Canadian base metal smelting operations is likely in the form of nickel sulphate, nickel subsulphide, and nickel oxide. From 10 to 77% of the nickel in the flue dusts of Canadian smelters was reported to be water-soluble. Releases of nickel (particularly to the atmosphere) from nickel mining, smelting, and refining operations have resulted in accumulations of nickel at concentrations above normal background values in surface waters, lake sediments, and soils near Sudbury, Ontario, and (based on results of older studies) in surface soils near Port Colborne, Ontario and Thompson, Manitoba.

Adverse effects have been reported in acute and chronic toxicity tests with a variety of aquatic organisms exposed to dissolved nickel at concentrations in the 24 to 50 µg/L range, and higher (Figure 1). For example, an avoidance threshold of 24 µg of Ni/L was reported for rainbow trout (Oncorhynchus mykiss), and life span was reduced in the cladoceran (Daphnia magna) at nickel concentrations of 40 µg/L. In addition, growth and cell numbers were reduced in two species of alga (Scenedesmus acuminatus and Anabaena inaequalis), and acute lethality was reported in the embryonic and larval stages of rainbow trout (Oncorhynchus mykiss) and narrow-mouthed toad (Gastrophryne carolinensis) at a concentration of 50 µg/L. Mean concentrations above these effect levels (that is in the 50 to several thousand µg/L range) have been reported recently (mid-to late-1980s) in both filtered and unfiltered samples of water from lakes within a radius of 20 km or more of Sudbury that have been affected by inputs of airborne nickel from local smelters, and in filtered pond waters near Smoking Hills, NWT (Figure 1). Results of studies in the Sudbury area indicate that most (95%) of the nickel in lake waters is in dissolved and hence bioavailable forms.

Although relatively high mean concentrations of total nickel (>4,000 µg/g) have been found in sediments from some Canadian lakes and rivers (Figure 2), spiked-sediment bioassays reporting dose-response relationships for nickel were not identified, and consequently, effect thresholds for sensitive freshwater benthic organisms could not be estimated. In a field co-occurrence study in the Great Lakes region, however, 95% of known invertebrate species were absent from sediments with nickel concentrations of ≥ 75 µg/g (d.w.) (Figure 2).

Adverse effects have been reported in terrestrial plants and microorganisms exposed to nickel in soil. Reduced yields occurred in several types of agricultural plants (lettuce, oats, wheat, mustard, and alfalfa) grown in acidic soils containing from 50 to about 100 µg/g of nickel added in soluble form (NiC1₂ or NiSO₄) (Figure 3). Furthermore, microbially mediated processes (nitrification and nitrogen mineralization), and growth and survival of several species of soil microorganisms (including Agrobacter radiobacter, Bacillus megaterium, Cryptococcus terreus, and Torulopsis glabrata) were adversely affected when 50 to 250 µg/g of nickel were added as NiC1₂ or NiSO₄ to acidic soils. As indicated in Figure 3, concentrations of total nickel equal to or greater than these effect levels have been reported near nickel smelting and/or refining operations at Sudbury and Port Colborne, Ontario and Thompson, Manitoba, as well as in naturally nickel-enriched soils in western Newfoundland, and near Thetford Mines, Quebec, and Ferguson Lake, Northwest Territories.

The bioavailability of nickel in soils varies, depending in particular upon the forms of nickel present and the soil pH. Nickel that is bound in the lattice of naturally occurring silicate minerals (e.g., olivine or pyroxenes) is relatively unavailable for uptake by plants compared to water-soluble forms, such as nickel sulphate, which may be deposited on surface soils from the atmosphere. In general, bioavailability increases with decreasing soil pH. In acidic soils, nickel-bearing sulphide and, to a lesser extent, silicate minerals (and possibly nickel oxide) can dissolve over time, and relatively little nickel is removed from soil pore waters by adsorption processes. Nickel complexed by organic ligands dissolved in soil pore waters is expected to be less bioavailable than free nickel ions.

Because of the low pHs (≤ 5.0) in nickel-enriched soils near the smelters at Sudbury, concentrations of bioavailable nickel (i.e., soluble forms of nickel and dissolved nickel in soil pore waters) in these soils are expected to be relatively high. In one recent study, the concentration of nickel in samples of organic-rich pore water from wetland soils collected within a radius of about 40 km of Sudbury ranged from 0.6 to 22.6 mg/L; the mean value was 3.5 mg/L (Figure 4). These measured values are within the range of values calculated (based on recent data on mean water-extractable nickel levels) for some mineral soils near smelters at Sudbury (i.e., 2.0 to 15 mg of Ni/L). The bioavailability of nickel in the pore waters of the wetland soils may be reduced relative to the mineral soils, however, because of complexation with dissolved organic ligands.

Both the measured and calculated pore water concentrations are similar to concentrations (i.e., 2.0 mg of Ni/L and higher) that have been reported to cause adverse effects (e.g., chlorosis, reduced yields, and reduced root growth) in sensitive plants (including tomato, broad bean, barley, and oats) grown in nutrient solutions (Figure 4).

Concentrations of nickel in plant tissues also provide an indication of the concentrations of bioavailable forms of nickel in the soils in which they are growing. Elevated concentrations of nickel have been reported in vegetables (lettuce, cabbage, celery, beets, and radish) grown in the early 1980s in organic soils near Port Colborne, Ontario [mean value of 64 to 290 µg/g (d.w.)]; in lawn grass, timothy, and oats collected in the early 1980s near Sudbury, Ontario [mean values of about 100 µg/g (d.w.)]; in various arctic plants growing in soil near sulphide ore bodies at Ferguson Lake, NWT [mean values from 35 to 60 µg/g (d.w.)]; and in leaves of native trees near an outcrop of ultramafic bedrock near Thetford Mines, Quebec [mean values from 10 to 20 µg/g (d.w.)] (Figure 5). All vegetables grown in soils near Port Colborne, and the lawn grass, timothy, and oats near Sudbury showed evidence of injury (e.g., reduced yield, stunted growth, chlorosis, and necrosis), which was attributed to exposure to high concentrations of nickel in soil. Furthermore, concentrations of nickel in native vegetation growing in naturally nickel-enriched soils were within the range reported to cause harm (including reduced growth) to various types of agricultural plants (Figure 5).

Recent data that would permit estimation of exposure of wild mammals to nickel were not identified. However, worst-case exposure scenarios were developed for aquatic and terrestrial avian species using maximum concentrations from early studies near Sudbury, Ontario (which may be one or two orders of magnitude higher than current levels).

The model aquatic avian species that was chosen for consideration is the mallard duck (Anas platyrhynchos). Prefledged mallard ducklings consume primarily invertebrates, while older ducklings and adults (with the exception of laying females) have a diet consisting primarily of plant material such as grass, bulrush (Scirpus) seeds, and seeds and tubers of pondweed (Potamogeton) (Chura, 1961). The mean concentration of nickel in insect larvae in 1984 in the Wanapitei region near Sudbury was 22.3 µg/g (d.w.) (Krantzberg, 1985). Similarly, concentrations of nickel in zooplankton from 6 of 7 lakes sampled near Sudbury were less than 25 µg/g (d.w.) (Yan and Mackie, 1989). These levels are more than an order of magnitude lower than the lowest level causing effects in ducklings [i.e., 300 µg/g (d.w.) for 3 weeks caused a decreased growth rate]. The highest mean concentration of nickel in aquatic plants near Sudbury in the 1970s was 290 µg/g (d.w.) in aquatic weeds such as Elodea canadensis and Potamogeton richardsonii (Hutchinson et al., 1976). Although effect levels for free-living birds have not been established, no effects were observed in a laboratory study with adult mallards fed a diet containing nickel at 800 µg/g (d.w.) for 90 days. Thus, levels of nickel in aquatic plants are not expected to be harmful to mallard ducks.

Similarly, for terrestrial birds, dietary exposure of ruffed grouse (Bonasa umbellus) can be estimated. Levels in aspen (Populus tremula) leaves from the crops of ruffed grouse near Sudbury ranged from 61.7 µg/g (d.w.) in May 1980 to 136 µg/g (d.w.) in September 1980 (Rose and Parker, 1983). Although feeding studies in this species have not been identified, based on the mallard feeding study, no effects on ruffed grouse are expected at levels present in aspen.

In conclusion, although nickel concentrations in the food of Canadian aquatic and terrestrial birds are likely not high enough (based on worst-case scenarios) to cause harmful effects, concentrations of dissolved inorganic nickel in Canadian surface waters are within the range that may have harmful effects on sensitive pelagic (i.e., water-column) organisms near nickel smelting and refining operations and near natural sources. Furthermore, concentrations of dissolved and soluble forms of inorganic nickel in surface soils contaminated by nickel smelting and refining, and in some areas where soils are naturally nickel-enriched, are within the range that may cause harmful effects to sensitive terrestrial plants as well as soil microbial populations in Canada. Therefore, on the basis of the available data, dissolved and soluble* forms of inorganic nickel are entering or may enter the environment in a quantity or concentration or under conditions that are having or may have a harmful effect on the environment.

3.2 CEPA 11(b) Environment on Which Human Life Depends

Nickel occurs at low concentrations in suspended particulate material in the atmosphere (typically about 5 ng/m³), has an atmospheric residence time of 5 to 8 days, and does not absorb infrared radiation. The only significant gaseous nickel compound, nickel carbonyl, degrades in air with a half-life of less than 1 minute. Consequently, "nickel and its compounds" are not expected to contribute to global warming or the depletion of stratospheric ozone.

Therefore, on the basis of available data, the substance "nickel and its compounds" does not enter the environment in a quantity or concentration or under conditions that constitute or may constitute a danger to the environment on which human life depends.

3.3 CEPA 11(c) Human Life or Health

Exposure. Estimates of the average daily intake of nickel (on a per body weight basis) for the general population in Canada are presented in Table 1. Due to the lack of identified data on the speciation of nickel in various environmental media, it was not possible to estimate the exposure of the general population to individual nickel compounds. Therefore, estimated values refer to total nickel. Based on these estimates, the principal route of nickel intake for all age groups is from ingestion of food, followed by drinking water, soil (particularly in infants and young children), and inhalation in air, though it should be noted that absorption following inhalation is greater than that for ingestion. Inhalation of cigarette smoke may increase total daily intake by 0.12 and 0.15 µg/[kg (b.w.) · d). Exposure to nickel may also occur from household products (Kuligowski and Halperin, 1992; Nava et al., 1987); however, available information is considered insufficient to permit quantification of exposure to nickel from such sources.

Table 1 Estimated Average Daily Intake of Nickel for the General Population in Canada

Mediuma	Estimated Daily Intake {µg/[kg(b.w.) · d]}
	0 to 0.5 yrb	0.5 to 4 yrc	5 to 11 yrd	12 to 19 yre	20 to 70 yrf
Ambient Air	0.0003 to 0.006	0.0004 to 0.008	0.0004 to 0.009	0.0004 to 0.007	0.0003 to 0.007
Water	0.02 to 0.77	0.01 to 0.44	0.007 to 0.24	0.005 to 0.16	0.004 to 0.15
Food	22	16	10	5.7	4.4
Soil	0.04 to 0.25	0.03 to 0.19	0.01 to 0.06	0.003 to 0.018	0.002 to 0.014
Tobacco Smokingg	-	-	-	0.15	0.12

^a Mean concentrations in ambient air based on a survey of Canadian cities were 0.001 to 0.02 µg/m³(Dann, 1991a;b). Mean concentrations in drinking water were 0.2 to 7.2 µg/L based on a range of mean concentrations of nickel reported in Ontario (Jenkins, 1992) which are similar to those reported elsewhere in Canada (Environment Canada, 1989a;b;c;d; Mineraux Noranda Inc., 1992; Moon et al., 1988). Intake in food was estimated based on concentrations of nickel in the various food types (NHW, 1992) multiplied by the age-specific food intakes from the Nutrition Canada Survey (EHD, 1992). No suitable data were identified to estimate intake of nickel by infants through breast milk. Mean concentrations of nickel in the soil in uncontaminated regions were 8 to 50 µg/g dry weight (see supporting documentation).
^b Weighs 7 kg, breathes 2 m³of air, drinks 0.75 L of water, and ingests 35 mg of soil daily (EHD, 1992).
^c Weighs 13 kg, breathes 5 m³of air, drinks 0.8 L of water, and ingests 50 mg of soil daily (EHD, 1992).
^d Weighs 27 kg, breathes 12 m³of air, drinks 0.9 L of water, and ingests 35 mg of soil daily (EHD, 1992).
^e Weighs 57 kg, breathes 21 m³of air, drinks 1.3 L of water, and ingests 20 mg of soil daily (EHD, 1992).
^f Weighs 70 kg, breathes 23 m³of air, drinks 1.5 L of water, and ingests 20 mg of soil daily (EHD, 1992).
^g Based on estimated mean nickel content of mainstream cigarette smoke of 0.43 µg per Canadian cigarette (Labstat Incorporated, 1991) and 20 cigarettes smoked per day (Kaiserman, 1992).

People residing in the vicinity of point sources may be exposed to higher levels of nickel in food, air, soil, and water than the general population. Based on comparison of the limited available data on concentrations of nickel in foodstuffs in the vicinity of point sources (Frank et al., 1982; McIlveen and Balsillie, 1977, in NRCC, 1981; Temple, 1978, in NRCC, 1981; Warren et al., 1971) with those determined in the total diet survey (NHW, 1992), it is possible that intake from food may be elevated for populations residing in the vicinity of industrial sources. Available data were considered insufficient, however, to quantitatively estimate intake in food for populations under such conditions. For purposes of estimation of exposure, therefore, it was considered to be similar to that of the general population. Based on the mean values reported in a limited early study of ambient air in the vicinity of point sources, the estimated intake in air was similar to that in the general population; however, based on maximum recorded values in this survey, intake in air in the vicinity of point sources may be considerably greater than that for the general population. Estimated mean intakes in such areas may range from 0.05 to 1.9 µg/[kg (b.w.) · d] in soil and from 0.6 to 12 µg/[kg (b.w.) · d] in water, with the greatest intake being in young children (Table 2).

Effects. In epidemiological studies in exposed human populations and in toxicological studies in experimental animals, the respiratory system appears to be the critical target for adverse effects following exposure by inhalation to nickel. In view of the serious nature of the adverse health impact of cancer, carcinogenicity is considered to be one of the most critical endpoints for assessment of whether "nickel and its compounds" (specifically metallic, "oxidic", "sulphidic", and "soluble" nickel) are "toxic" under Paragraph 11(c) of CEPA. The weight of evidence for the carcinogenicity of these forms of nickel has been assessed, therefore, based on the criteria developed for the "Determination of 'Toxic' under Paragraph 11(c) of the Canadian Environmental Protection Act" (EHD, 1992).

In the following assessment of the weight of evidence for carcinogenicity, the studies considered most relevant to the assessment of hazard and risk to the general population are those in epidemiological studies of human populations. Toxicological studies in animal species considered most relevant to the assessment are those in which routes of exposure were similar to those by which humans are exposed in the general environment (i.e., inhalation and ingestion). Results of investigations in which animals have been exposed intratracheally (which bypasses natural defence mechanisms of the lung), intraperitoneally or intrapleurally, or by direct injection into specific tissues are considered as supporting data only.

Table 2 Estimated Average Daily Intake of Nickel by Canadians Living Near Point Sources

Mediuma	Estimated Daily Intake {µg/[kg(b.w.) · d]}
	0 to 0.5 yrb	0.5 to 4 yrc	5 to 11 yrd	12 to 19 yre	20 to 70 yrf
Ambient Air	0.006	0.008	0.009	0.008	0.007
Water	2.8 to 12	1.6 to 6.7	0.87 to 3.6	0.60 to 2.5	0.56 to 2.3
Food	22	16	10	5.7	4.4
Soil	0.83 to 1.9	0.63 to 1.5	0.21 to 0.49	0.06 to 0.13	0.05 to 0.11

1. Mean concentrations in various media were those reported in the vicinity of Sudbury: 0.021 µg/m³in ambient air based on an early study covering the period from 1978 to 1980 (Chan and Lusis, 1986); 26.2 to 108.3 µg/L in drinking water at two water treatment plants (Jenkins, 1992); 165 to 380 mg/kg dry weight in soil (Maxwell, 1991). Intake in food was considered to be the same as that for the general population (Table 1).
2. Weighs 7 kg, breathes 2 m³of air, drinks 0.75 L of water, and ingests 35 mg of soil daily (EHD, 1992).
3. Weighs 13 kg, breathes 5 m³of air, drinks 0.8 L of water, and ingests 50 mg of soil daily (EHD, 1992).
4. Weighs 27 kg, breathes 12 m³of air, drinks 0.9 L of water, and ingests 35 mg of soil daily (EHD, 1992).
5. Weighs 57 kg, breathes 21 m³of air, drinks 1.3 L of water, and ingests 20 mg of soil daily (EHD, 1992).
6. Weighs 70 kg, breathes 23 m³of air, drinks 1.5 L of water, and ingests 20 mg of soil daily (EHD, 1992).

Based on an extensive analysis of recent follow-ups of the principal exposed cohorts, mortality due to lung cancer was significantly increased in sinter plant workers at three INCO facilities in Ontario who were exposed primarily to "oxidic" and "sulphidic" nickel, while mortality due to nasal cancer was significantly elevated at the two larger of the three facilities (Copper Cliff and Port Colborne). Mortality due to these causes increased with duration of employment in these two larger plants, and with estimates of cumulative exposure derived from data presented in the published report. In addition, nasal cancer mortality was increased in electrolysis workers at the Port Colborne plant who were exposed primarily to "soluble" nickel (Doll et al., 1990).

Mortality due to lung and nasal cancer was also significantly increased in workers at the Falconbridge nickel refinery in Kristiansand, Norway. Lung cancer mortality increased with duration of employment and with cumulative exposure. When the data were analyzed by various species of nickel compounds, the elevated mortality due to lung cancer was associated with exposure to "soluble" nickel, while excess nasal cancer mortality was related to exposure to "oxidic" nickel (Doll et al., 1990).

Similarly, in the cohort of the Mond/INCO refinery at Clydach, mortality due to lung and nasal cancer increased both with duration of employment and estimated cumulative exposure in the subgroup of workers exposed to high concentrations of "oxidic", "sulphidic", metallic, and "soluble" nickel. However, based on the cross-classification by cumulative exposure to various forms of nickel, increased mortality due to lung or nasal cancer was most strongly associated with exposure to "sulphidic" nickel or a combination of "sulphidic", "oxidic", or "soluble" nickel, but not metallic nickel. In addition, there was a decrease in lung cancer mortality following a reduction in exposure to "soluble" and "sulphidic" nickel compounds. (Doll et al., 1990).

There was also elevated mortality from lung cancer in workers exposed mainly to "sulphidic" nickel and to low levels of mineral-based nickel, iron-" sulphidic" nickel, "oxidic" nickel, and "soluble" nickel at the Falconbridge mining and smelting operations in Sudbury (Doll et al., 1990), although the increase could not be unequivocally attributed to nickel. Some evidence of increased lung cancer risk was noted in workers exposed to "soluble" nickel and "sulphidic" nickel, respectively, at the Outokumptu Oy refinery in Finland and the Huntingdon Alloy facility in West Virginia (Doll et al., 1990). However, in studies in small numbers of workers at mining and smelting operations in Oregon and New Caledonia, who were mainly exposed to "oxidic" nickel at levels much lower than those reported in other facilities in which increased mortality due to lung and nasal cancer was observed, there was little convincing evidence of increased mortality due to lung or nasal cancer (Doll et al., 1990). Similarly, exposure to low levels of "oxidic" or metallic nickel resulted in no increase in the number of lung or nasal cancer deaths in a group of workers at the Henry Wiggin Alloy plant in England (Doll et al. 1990). Mortality due to lung or nasal cancer was not elevated in two small cohorts of workers exposed to metallic nickel at the Oak Ridge Gaseous Diffusion plant in Tennessee and the Sherritt Gordon hydrometallurgical nickel refinery in Fort Saskatchewan, Alberta, although it should be noted that the number of expected cases in the former cohort was very small (n = 3) (Doll et al., 1990; Egedahl et al., 1991).

All of the available epidemiological studies are limited. There are few data on cumulative exposure (or limited documentation to serve as a basis for estimation of cumulative exposure) and little information on exposure to other substances, which was not taken into account in the analyses. Moreover, information on the smoking habits of the subjects was not presented in any of these investigations. Nevertheless, variations in smoking habits are unlikely to explain the large observed excesses in respiratory cancer (Blair et al., 1985; Siemiatycki et al., 1988). Furthermore, the total number of deaths recorded in most of these studies is still only a small proportion of those included in the cohort. Despite the limitations of these studies, many of which would have contributed to the obfuscation of an association between exposure to nickel and the development of cancer, there is sufficient weight of evidence in several studies (i.e., the most sensitive) for an association between exposure to "oxidic", "sulphidic", and "soluble" nickel and respiratory and nasal cancer. In addition, there was evidence of exposure-response relationships for all three forms and some indication that a reduction in occupational exposure to "sulphidic" and "soluble" nickel resulted in a decrease in mortality due to lung cancer. However, there is no convincing evidence that occupational exposure to metallic nickel was associated with cancer. Although not as well documented, there is no consistent evidence that cancers at sites other than the lung and nose may be associated with occupational exposure to nickel (Doll et al., 1990).

Available epidemiological data on the potential association of ingested nickel and cancer are inconclusive, and do not contribute to assessment of the weight of evidence for carcinogenicity.

An increased frequency of chromosomal aberrations has been observed in the peripheral lymphocytes of chemical plant workers exposed to "soluble" nickel and nickel refinery workers exposed to "oxidic", "soluble", and "sulphidic" nickel (combined) (Senft et al., 1992; Waksvik et al., 1984; Waksvik and Boysen, 1982), with some indication of a dose response in the study of Senft et al. (1992). An elevated frequency of chromosomal aberrations and sister chromatid exchanges was also reported in electroplaters (form of nickel unknown) (Deng et al., 1988). Mixed results have been obtained in two studies in welders (form of nickel not specified) (Popp et al., 1991; Elias et al., 1989). Most of these studies, however, involved small numbers of workers (maximum number of exposed individuals was 39) who were generally also exposed to a number of other metals (e.g., iron, manganese, and chromium during welding, chromium in an electroplating refinery, copper and other metals in a nickel refinery).

Although there was a clear increase in the incidence of lung tumours in rats administered metallic nickel powder by intratracheal instillation (Pott et al., 1987), the carcinogenicity of this form of nickel has not been investigated in adequate, more relevant, inhalation studies. Increased incidences of tumours have also been induced at the site of administration in limited studies in experimental animals exposed to metallic nickel via routes less relevant to environmental exposure (e.g., intrapleural, subcutaneous, intratesticular, intramuscular, intraperitoneal, and intrarenal injection) (IARC, 1990).

Chromosomal aberrations in the bone marrow were induced by a metallic nickel aerosol derived from nickel refinery waste (repeated inhalation exposure) in rats (Chorvatovicova and Kovacikova, 1992). Metallic nickel did not induce chromosomal aberrations in cultured human cells but it transformed animal cells in vitro (IARC, 1990).

Nickel subsulphide induced an increased incidence of lung tumours in rats exposed by inhalation for approximately 80 weeks (Ottolenghi et al., 1974) and there was some weak evidence of a similar increase in the incidence of lung tumours reported in rats exposed to a "sulphidic" nickel-containing dust for 6 months in a limited study for which the published account was inadequate for assessment (Saknyn and Blokhin, 1978). Following intratracheal administration, there was a clear increase in the incidence of lung tumours in rats administered nickel subsulphide in one study (Pott et al., 1987), but not in mice in two other investigations exposed to lower doses (Fisher et al., 1986; McNeill et al., 1990). In addition, local tumours were observed in animals administered "sulphidic" nickel by routes other than ingestion or inhalation (IARC, 1990).

Nickel subsulphide administered by intraperitoneal injection produced chromosomal damage (micronuclei) in mice (Arrouijal et al., 1990). "Sulphidic" nickel compounds produced chromosome aberrations, sister chromatid exchanges, and cell transformation in numerous in vitro systems (IARC, 1990; IPCS, 1991).

There was an increase in the incidence of lung tumours in rats administered nickel oxide by intratracheal instillation (Pott et al., 1987); however, no evidence of cancer was observed in a limited study in hamsters exposed by inhalation (Wehner et al., 1975). "Oxidic" nickel compounds have also induced tumours at the site of injection in rats and mice (IARC, 1990).

"Oxidic" nickel induced cell transformation in cultured rodent cells. However, it did not induce chromosomal aberrations in a study in cultured human cells (IARC, 1990).

There was no evidence of cancer in studies in hamsters exposed to nickel acetate-enriched fly ash by inhalation (Wehner et al., 1981). In studies in which rats and mice were administered nickel sulphate or other "soluble" nickel salts in the diet or drinking water, there have been no increases in tumour incidence; however, all of these studies are considered to be inadequate for an assessment of carcinogenicity, due to small group sizes, limited examination of tissues and/or poor documentation of the results (Ambrose et al., 1976; Dieter et al., 1988; Schroeder and Mitchener, 1975; Schroeder et al., 1964; 1974). Hydrated nickel acetate induced lung tumours in mice following repeated intraperitoneal injection (Poirier et al., 1984; Stoner et al., 1976). There is some limited evidence that "soluble" nickel compounds induced local tumours following administration by routes less relevant to environmental exposure (IARC, 1990).

Although the weight of evidence indicates that various "soluble" nickel salts were not mutagenic in a range of bacterial assays, "soluble" nickel salts produced chromosome aberrations, sister chromatid exchanges, and cell transformation in numerous in vitro systems (IARC, 1990). In addition, chromosomal aberrations in the bone marrow were induced by nickel chloride (single intraperitoneal injection) in mice (Dhir et al., 1991; Mohanty, 1987) and hamsters (Chorvatovicova, 1983). There was also an increased frequency of micronucleated polychromatic erythrocytes in mice following oral administration (Sobti and Gill, 1989) and intraperitoneal injection (Deknudt and Leonard, 1982; Dhir et al., 1991) of nickel chloride, nickel sulphate, or nickel nitrate and induction of DNA damage in the kidneys and lungs of rats administered nickel carbonate intraperitoneally (Ciccarelli and Wetterhahn, 1982). There was no convincing evidence of activity of nickel chloride and nickel nitrate administered by intraperitoneal injection in dominant lethal mutation assays in mice (Deknudt and Leonard, 1982; Jacquet and Mayence, 1982).

In summary, there was no evidence that exposure to metallic nickel was associated with increased mortality due to lung or nasal cancer in two small cohorts of workers exposed primarily to this form of nickel (Doll et al., 1990) and in cross-classification analyses in two larger cohorts (Doll et al., 1990). While there is some evidence that metallic nickel may be carcinogenic in experimental animals exposed by direct intratracheal instillation (Pott et al., 1987), the carcinogenicity of this form of nickel has not been investigated in adequate inhalation studies for which exposure conditions are more relevant to assessment of effects in humans. Due to the limited sensitivity of available epidemiological studies in which the association between exposure to metallic nickel and cancer in occupationally exposed populations has been investigated, and the lack of identified adequate carcinogenicity bioassays in which experimental animals have been exposed to metallic nickel by inhalation, metallic nickel is classified in Group VI ("Unclassifiable with Respect to Carcinogenicity in Humans") of the classification scheme developed for the determination of "toxic" under Paragraph 11(c) of CEPA (EHD, 1992). For compounds classified in Group VI, a tolerable daily intake or concentration to which it is believed that a person can be exposed daily over a lifetime without deleterious effect is generally developed by division of a relevant No-Observed-(Adverse)-Effect Level [NO(A)EL] or Lowest-Observed-(Adverse)-Effect Level [LO(A)EL] for non-neoplastic effects in animal species by an uncertainty factor. Minimal effects on the morphology and function of alveolar cells have been observed in rabbits exposed to concentrations of metallic nickel as low as 0.1 mg/m³(Camner and Johansson, 1992; Curstedt et al., 1983; Johansson et al., 1983; Lundborg and Camner, 1982). Concentrations of total nickel in ambient air in Canada are more than 5000 times less than this value. Moreover, metallic nickel is believed to comprise only a small proportion of the total nickel present in ambient air in Canada (MacLatchy, 1992), although quantitative information on speciation in the general environment was not identified.

Therefore, metallic nickel is not considered to be entering the environment in a quantity or concentration or under conditions that may constitute a danger in Canada to human life or health.

There is sufficient and consistent evidence of the carcinogenicity of "oxidic", "sulphidic", and "soluble" nickel in adequate epidemiological studies in different types of exposed workers and some weak evidence of genotoxicity in limited epidemiological studies. Although there may have been concomitant exposure to other compounds in these studies, the common predisposing factors in the various groups of workers examined appear to be these groups of nickel compounds. In addition, there is some supportive evidence of carcinogenicity and genotoxicity of these forms of nickel in principally limited studies in animal species. Therefore, each of "oxidic", "sulphidic", and "soluble" nickel* has been included in Group I ("Carcinogenic to Humans") of the classification scheme developed for the determination of "toxic" under Paragraph 11(c) of CEPA (EHD, 1992).

For such substances, where data permit, the estimated exposure in relevant environmental media is compared to quantitative estimates of cancer potency, expressed as the concentration or dose that induces a 5% increase in the incidence of or mortality due to relevant tumours (TD_0.05) (i.e., exposure/potency indices), to characterize risk and provide guidance for further action (i.e., analysis of options to reduce exposure) under CEPA (EHD, 1992).

The data considered most relevant to the quantification of the cancer potency associated with exposure to inorganic nickel compounds in the general environment are those obtained in epidemiological studies in occupationally exposed populations, since the weight of evidence of such an association in these studies is convincing. This approach also obviates the need for interspecies extrapolation.

The epidemiological studies that provide sufficient information to serve as a basis for quantitative estimation of the carcinogenic potency of inhaled inorganic nickel are those of large cohorts (n = 3250 to 54509) of exposed workers at two nickel refineries for whom the most extensive information on exposure is available: the INCO mining, smelting, and refinery operations in Ontario, and the Falconbridge refineries in Kristiansand, Norway (Doll et al., 1990). Estimates of the carcinogenic potency of "oxidic", "sulphidic", and "soluble" nickel (combined), based on results at the INCO mining, smelting, and refinery operations in Ontario were considered the most relevant and reliable for several reasons: the cohorts were relatively large (e.g., total expected numbers of deaths of Copper Cliff sinter plant workers with 15 or more years since first exposure due to lung cancer was approximately 20); there was clear evidence of increased lung and nasal cancer mortality with increasing duration of exposure in the sinter workers, and there was no exposure to metallic nickel (i.e., the estimates of total concentrations of nickel did not include a form of nickel for which there is no convincing evidence of carcinogenicity). Although the potency of the various species may vary considerably, the TD_0.05s estimated on the basis of the INCO cohort are based on "oxidic", "sulphidic", and "soluble" nickel (combined) since available data do not permit separate estimates for each of the groups of compounds. This is justified on the basis that all three forms are likely to be present in the general environment.

The Kristiansand cohort consisted of two clearly defined working groups, i.e., electrolysis workers with no employment in other high exposure departments and those employed in the roasting, smelting, and calcining department. There was little exposure to metallic nickel in both groups. Based on the data presented for these workers, TD_0.05s may be developed for "oxidic", "sulphidic", and "soluble" nickel (combined), and "soluble" nickel (specifically).

A detailed description of the mathematical derivation of the constant concentration that corresponded to a 5% increase in mortality due to lung or nasal cancer (TD0_0.05), based on the data reported by Doll et al. (1990), is presented in the Appendix of the supporting documentation. The age-specific death rate for lung cancer observed in the cohorts of the Copper Cliff sinter plant and Coniston sinter plant was assumed to be a linear function of the cumulative exposure to total nickel, whereas the age-specific death rate for lung cancer reported in the cohorts of Port Colborne nickel refinery and Kristiansand nickel refinery workers was assumed to be an exponential function of the cumulative exposure to total nickel. The age-specific death rate was also assumed to be multiplicative to the death rate for the general population. The increase in probability of death due to a constant lifetime exposure to nickel has been determined, based on the assumption that there are no competing causes of death and a constant exposure for a period equal to the median survival time of 75 years. The estimates of the TD_0.05 for inhaled "oxidic", "sulphidic", and "soluble" nickel (combined) for lung cancer mortality ranged from 0.04 to 1.0 mg/m³. It should be noted that the TD_0.05s based on data for workers in the Clydach refinery (although the numbers of workers in each occupational group were small) would not be substantially different. The TD_0.05 for lung cancer mortality for "soluble" nickel, estimated based on data for the Kristiansand cohort, was also within this range of values (i.e., 0.07 mg/m³).

Corresponding calculated exposure/potency indices (EPIs) for the range of mean concentrations of total inorganic nickel reported in ambient air in several cities across Canada [0.001 to 0.02 µg/m³(Dann, 1991a;b)] range from 1.0 x 10^-6to 5.0 x 10^-4. Calculated EPIs, based on the TD_0.05s derived for nasal cancer for the Copper Cliff and Port Colborne cohorts, are less than those derived for lung cancer (i.e., 3.8 x 10^-7 to 7.6 x 10^-6 and 6.8 x 10^-7 to 1.4 x 10^-5, respectively). Based solely on considerations of potential health effects, therefore, the priority for further action (i.e, analysis of options to reduce exposure) would be considered to be moderate to high. Values calculated for populations residing in the vicinity of point sources based on early, limited available monitoring data are within the same range [i.e., the priority for further action is considered to be moderate to high based on a concentration of total inorganic nickel in ambient air of 0.021 µg/m³determined in an early survey in Sudbury (Chan and Lusis, 1986)].

It should be noted, however, that there are several limitations of the EPIs that should be considered in their interpretation. For example, the estimated concentrations of total airborne nickel at the INCO mining, smelting, and refinery operations were based on only a few industrial hygiene samples of the occupational environment taken in the later period of employment of study subjects. In addition, concomitant exposure to other compounds and smoking were not taken into account in the analyses. It should also be noted that there were few data on atmospheric concentrations of nickel in the Kristiansand plant before the early 1970s (the estimated concentrations of total airborne nickel for earlier periods were based largely on the subjective judgements of retired personnel) and expected numbers of deaths from lung and nasal cancer in this cohort were very small, i.e., the cohort was small (e.g., expected numbers of deaths from lung cancer in electrolysis workers with 15 or more years since first exposure ranged from 0.8 to 3.8). As well, only a small proportion of the cohorts studied had died at the time of the follow-up. Furthermore, although it is recognized that the potencies of the various forms of nickel are likely to vary, most of the available data were inadequate to permit calculation of separate potencies for each of the compounds, and no data are available on the speciation of nickel present in ambient air in Canada [although these three forms of nickel are likely present (IPCS, 1991)].

Based principally on the sufficient weight of evidence of carcinogenicity in occupationally exposed populations for the groups of compounds examined in a recent extensive epidemiological analysis and some limited supporting data on individual compounds in experimental animals, each of the groups * "oxidic" (including nickel oxide, nickel-copper oxide, nickel silicate oxides, and complex oxides), "sulphidic" (including nickel subsulphide), and "soluble" (primarily nickel sulphate and nickel chloride) nickel compounds has been classified as "Carcinogenic to Humans" (i.e., groups for which there is considered to be some probability of harm for the critical effect at any level of exposure). Each of these groups is, therefore, considered to be entering the environment in a quantity or concentration or under conditions that may constitute a danger in Canada to human life or health.

This approach is consistent with the objective that exposure to substances for which one of the critical effects is considered not to have a threshold should be reduced wherever possible and obviates the need to establish an arbitrary "de minimis" level of risk for the determination of "toxic" under the Act.

In addition to the documented carcinogenicity of "oxidic", "sulphidic", and "soluble" nickel in occupationally exposed human populations, nickel (mostly "soluble" compounds) induces allergic contact dermatitis in a proportion of the general population. Contact hypersensitivity following dermal application has also been induced in experimental animals (IPCS, 1991). No information has been identified on the proportion of the Canadian general population that is sensitized towards nickel. In a number of studies of the general population of other countries of similar economic and social character, however, the prevalence was 8 to 21.9% in females and 0.3 to 2.8% in males (Meding and Swanbeck, 1990; Menné et al., 1982; Peltonen, 1979; Prystowsky et al., 1979; Seidenari et al., 1990). The major cause of the sensitized state in the general population is believed to be contact with low quality jewellery, particularly earrings and other items, such as watch-straps.

The available epidemiological data on effects other than cancer and dermatological sensitivity for "oxidic", "sulphidic", and "soluble" nickel compounds are insufficient to serve as a basis for establishment of effect levels. However, Tolerable Daily Intakes (TDIs) or Concentrations (TDCs) developed on the basis of the somewhat limited data on non-neoplastic effects in animal species would, for some of these forms of nickel, be similar to the mean exposure of some subgroups in the population. For example, the Lowest-Observed-Adverse-Effect-Level {i.e., 1.3 mg of Ni/[kg(b.w.) · d] for an increased proportion of dead pups per litter} in a suitable study in animals ingesting "soluble" inorganic nickel compounds (Smith et al., 1993), is 36 to 260 times greater than estimated total intakes through ingestion for populations residing in the vicinity of point sources (i.e., less than the magnitude of an uncertainty factor that might be used in the derivation of a TDI). The lowest LOEL (0.02 mg/m³) for minimal respiratory effects in animals exposed to nickel oxide (Spiegelberg et al., 1984) or nickel sulphate (Dunnick et al., 1989) is less than 1000 times greater than concentrations of nickel in ambient air at some locations.

3.4 Conclusions

Based on these considerations, it has been concluded that dissolved and soluble* forms of inorganic nickel are entering or may enter the environment in a quantity or concentration or under conditions that are having or that may have a harmful effect on the environment. It has been concluded that the substance "nickel and its compounds" does not or may not enter the environment in a quantity or concentration or under conditions that constitute or that may constitute a danger to the environment on which human life depends. It has also been concluded that metallic nickel does not constitute a danger in Canada to human life or health, however each of the groups, "oxidic" (including nickel oxide, nickel-copper oxide, nickel silicate oxides, and complex oxides), "sulphidic" (including nickel subsulphide), and "soluble" (primarily nickel sulphate and nickel chloride) nickel compounds, as a whole, is entering the environment in a quantity or concentration or under conditions that may constitute a danger in Canada to human life or health.

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* The term "soluble" includes water-soluble forms of nickel (e.g., nickel sulphate and nickel chloride), as well as other more stable forms (e.g., nickel-hearing sulphide minerals and nickel oxide) that can dissolve under certain conditions of pH (e.g., acidic mine tailings) or redox potential (e.g., buried reducing sediment) in the environment.

* Based on the nature of the available data, this classification is considered to apply to the groups of "oxidic", "sulphidic", and "soluble" nickel compounds rather than to any specific compound within these groups.

* Based on the nature of available data, this assessment of these forms of nickel under Paragraph 11(c) of CEPA is considered to apply to the groups of "oxdic", "sulphidic", and "soluble" nickel compounds, rather than to any specific compound within these groups.

* The term "soluble" includes water-soluble forms of nickel (e.g., nickel sulphate and nickel chloride), as well as other more stable forms (e.g., nickel-bearing sulphide minerals and nickel oxide) that can dissolve under certain conditions of pH (e.g., acidic mine tailings) or redox potential (e.g., buried reducing sediment) in the environment.