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Description of key information

A series of retrospective cohort studies on female workers in a nickel refinery in USSR/Russia was made on various developmental/teratogenicity endpoints in order to correlate birth deficiencies with exposure to Nickel. The studies showed no significant statistical relationship between exposure to Nickel and the observed increased incidence of perinatal effects in human infants.
The results from the investigation of reproductive performance in a nickel refinery in Russia are important since spontaneous abortion in humans would most closely approximate the observation of perinatal lethality associated with nickel exposure in rodents. Further evidence that nickel exposure is not adversely affecting the reproduction of these women is provided by the lack of a “small-for-gestational-age” finding and also the lack of an association of male genital malformations with nickel exposure. Both of these findings are considered “sentinel” effects for reproductive toxicity in humans.
Even though a potential reproductive hazard has been demonstrated by animal studies from exposure to nickel compounds, the risk of such exposures causing adverse reproductive effects in humans is too small to be determined by modern epidemiological assessment. Since this Russian cohort is the highest expsoed cohort of female workers identified in a global search, it is unlikely that future work will be able to improve the outcome of this body of work.
Studies on the effects of repeated inhalation exposure of human to some of the constituents of Ferronickel slags showed that for most of them, chronic exposure to dust or fumes via the respiratory tract is not connected with systemic toxicity. Iron and aluminium metals and compounds were studied and the pneumonoconiosis that can result from continued inhalation of iron or aluminium is of no concern with the current industrial practices. Results on Nickel were inconclusive, while CaO induces local effects and Cr(III) is of negligible toxicity.

Additional information

Repeated Dose Inhalation Toxicity

From studies on Iron Oxide chronic toxicity, it can be deduced that fibrosis is not a requisite in siderosis. This is the outcome of the actual review of McLaughlin, 1951, who makes the following important remarks regarding siderosis which are valid until today:

  1. Iron can be deposited in the lungs from the inspired air resulting in siderosis.

  2. In siderosis, the aggregates of iron are situated in the peribrochial and periarterial lymph spaces

  3. No fibrosis is found in relation to the deposits of iron

Nowadays, siderosis is considered to be a simple pneumonoconiosis with good prognosis. The frequent monitoring of personnel enforcing preventive steps and reducing the concentrations of metal dust in the work environment help to reduce the incidence of siderosis among metal workers (Gurzau et al, 2003).

A study on the chronic toxicity of Calcium Oxide is available and mentioned in Table 24, above (Toren et al, 1996). In general, the toxicity of CaO is directly related to its irritating potential. It is known that CaO is strongly irritating to skin. It reacts with skin and mucous membranes on contact by splitting fat and proteins. CaO damages mucous membranes by generating heat and dehydrating the tissues as the particles react with the moisture of the skin, and by the alkalinity of calcium hydroxide that is formed in this process (Swed. Occupational Standards, 1999; US Dept of Health CaO). The study on chronic exposure of workers to CaO also verifies the irritating potential of this substance which was manifested at dust concentrations of 1.2mg/m3. However, in the slags, CaO renders its inherent irritation potentila invalid. This has been verified in the acute oral and inhalation toxicity experiments on Ferronickel Slags, as well as in the skin and eye irritation experiments and in the skin sensitisation experiment. It is thus concluded that CaO is of negligible toxicity.

Chromium (III) is of negligible toxicity to humans and other mammals.

From studies on chronic toxicity of Nickel metal and Nickel salts it can be deduced that:1) non-malignant deaths in groups occupationally exposed to nickel were more, equal or even fewer than the general population. The results thus are inconclusive. A strong healthy worker effect bias is a possible confounding factor when the referent group is the general population of same race and sex: 2) non-lethal respiratory effects (besides cancer) have been observed in groups occupationally exposed to nickel compounds. Co-presence of many nickel species and of other metals as well as poor characterization of ambient levels of nickel do not render these studies suitable for robust risk characterization. It has been verified however from the aforementioned animal studies that the most water soluble Ni substances are also the most toxic for the lung when inhaled (see also NTP, 1996a).

From studies on chronic toxicity of aluminium oxide and other aluminium compounds it can be deduced that compromised respiratory function and/or asthmatic reactions may be elevated in industrial environments characterised by the presence of aluminium species. However, most of the studies have been performed in environments characterized by a plethora of contaminants besides aluminium dust (potrooms). Quoting Krewski et al, 2007 “it seems that most respiratory problems experienced by aluminium workers - potroom workers, foundry workers, welders - were not due to exposure to aluminium compounds but rather to other substances in the workplace. The exception appears to be workers who were exposed to very fine aluminium dust who developed pulmonary fibrosis; based on reports in the literature this seems to have occurred relatively rarely-precise figures are not available”. An overview of these case studies of severe lung diseases (fibrosis, alveolar proteinosis, granulomatosis and chronic obstructive lung disease) can be found in Krewski et al, 1997 pp 170-172. Most of the exposures that resulted in most severe outcomes occurred in Germany in World War II in heavily contaminated industrial settings. Concentrations of 50-100 mg/m3 of aluminium have then lead to the fibrotic disease aluminosis. Under today's working conditions lung fibrosis induced by aluminium dust is not expected to occur anymore, as long as relevant OELs are followed.

Toxicity to reproduction

The toxicity of inhalation of water-soluble Ni salts (which are more bioavailable than Ni metal) on embryonic developmental parameters has been extensively studied on a population of female workers in a Ni refinery.The odds ratio (OR) of delivering a newborn with a genital malformation (undescended testes or hypospadias) for the women working in nickel exposed areas did not reveal a difference between these groups and the general population of the town of the Ni refinery. Furthermorethere was no adverse effect of maternal occupational exposure to water-soluble Ni in the first part of pregnancy on the risk of delivering a chromosomally normal SGA (small for gestational age) new born.There was also no adverse effect of maternal exposure during the periconception period and early pregnancy to water-soluble Ni on the risk of delivering a newborn with musculoskeletal deformities and malformations. Finally, another study on this population did not reveal a statistical association between maternal exposure to water-soluble Ni in early pregnancy and the risk of self-reported spontaneous abortion