CADMIUM 45 3. HEALTH EFFECTS 3.1 INTRODUCTION The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and other interested individuals and groups with an overall perspective on the toxicology of cadmium. It contains descriptions and evaluations of toxicological studies and epidemiological investigations and provides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health. A glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile. The form of cadmium and the route of exposure can greatly affect the absorption and distribution of cadmium to various target sites, and therefore, the concentration at the target site and the severity of the observed effect. The mechanism of action, however, involves the cadmium cation’s effect on the target site, and the cation is the same regardless of the anionic species. For inhaled cadmium compounds, the size of the cadmium particle (i.e., fume or aerosol) can also affect the absorption and distribution. For oral exposures, cadmium chloride is most often tested in animal studies because of its high water solubility and the resulting high concentrations of cadmium delivered to target sites. Studies on cadmium bound to metallothionein are also of interest because cadmium-metallothionein complexes may have different toxic profiles and are found in relatively high levels in organ meats (e.g., liver and kidney). Cadmium oxide and cadmium carbonate, which are relatively insoluble in water (but may dissolve at gastric pH), appear to be similar in absorption and toxicity to soluble cadmium. There are fewer studies available on other forms of cadmium including insoluble forms in water such as cadmium sulfide (a yellow pigment) and cadmium selenium sulfide (a red pigment), and a soluble form, cadmium sulfate, which is less soluble in a closed air system where there is a limited amount of dissolved carbon dioxide. Chapter 4 lists the chemical and physical properties of several cadmium compounds. 3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE To help public health professionals and others address the needs of persons living or working near hazardous waste sites, the information in this section is organized first by route of exposure (inhalation, oral, and dermal) and then by health effect (death, systemic, immunological, neurological, reproductive, developmental, genotoxic, and carcinogenic effects). These data are discussed in terms of three exposure periods: acute (14 days or less), intermediate (15–364 days), and chronic (365 days or more). CADMIUM 46 3. HEALTH EFFECTS Levels of significant exposure for each route and duration are presented in tables and illustrated in figures. The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowest- observed-adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the studies. LOAELs have been classified into "less serious" or "serious" effects. "Serious" effects are those that evoke failure in a biological system and can lead to morbidity or mortality (e.g., acute respiratory distress or death). "Less serious" effects are those that are not expected to cause significant dysfunction or death, or those whose significance to the organism is not entirely clear. ATSDR acknowledges that a considerable amount of judgment may be required in establishing whether an end point should be classified as a NOAEL, "less serious" LOAEL, or "serious" LOAEL, and that in some cases, there will be insufficient data to decide whether the effect is indicative of significant dysfunction. However, the Agency has established guidelines and policies that are used to classify these end points. ATSDR believes that there is sufficient merit in this approach to warrant an attempt at distinguishing between "less serious" and "serious" effects. The distinction between "less serious" effects and "serious" effects is considered to be important because it helps the users of the profiles to identify levels of exposure at which major health effects start to appear. LOAELs or NOAELs should also help in determining whether or not the effects vary with dose and/or duration, and place into perspective the possible significance of these effects to human health. The significance of the exposure levels shown in the Levels of Significant Exposure (LSE) tables and figures may differ depending on the user's perspective. Public health officials and others concerned with appropriate actions to take at hazardous waste sites may want information on levels of exposure associated with more subtle effects in humans or animals (LOAELs) or exposure levels below which no adverse effects (NOAELs) have been observed. Estimates of levels posing minimal risk to humans (Minimal Risk Levels or MRLs) may be of interest to health professionals and citizens alike. Levels of exposure associated with carcinogenic effects (Cancer Effect Levels, CELs) of cadmium are indicated in Tables 3-1 and 3-6 and Figures 3-1 and 3-2. Because cancer effects could occur at lower exposure levels, Figure 3-1 also shows a range for the upper bound of estimated excess risks, ranging from a risk of 1 in 10,000 to 1 in 10,000,000 (10-4 to 10-7), as developed by EPA. A User's Guide has been provided at the end of this profile (see Appendix B). This guide should aid in the interpretation of the tables and figures for Levels of Significant Exposure and the MRLs. CADMIUM 47 3. HEALTH EFFECTS 3.2.1 Inhalation Exposure The information in this section on health effects of inhalation exposure to cadmium in humans is derived from studies of workers exposed to cadmium fume or dusts in industries such as smelting, battery manufacturing, soldering, and pigment production. Adverse effects of human exposure to cadmium were first established among workers in a cadmium battery factory (Friberg 1950). Workers are exposed occupationally to cadmium primarily by inhalation of fumes or dust. Some gastrointestinal tract exposure may also occur when dust is removed from the lungs by mucociliary clearance and subsequently swallowed, or by ingestion of dust on hands, cigarettes, or food (Adamsson et al. 1979). In experiments with animals, some ingestion may also occur from inhalation exposures by mucociliary clearance or from animal grooming. The primary form of cadmium in occupational exposures is cadmium oxide. Experimental studies in laboratory animals have used cadmium oxide, cadmium chloride, and occasionally other forms of cadmium such as cadmium sulfide and cadmium sulfate. In general, the different forms of cadmium have similar toxicological effects by the inhalation route, although quantitative differences may exist from different absorption and distribution characteristics, particularly for the less soluble cadmium pigments such as cadmium sulfide and cadmium selenium sulfide (Buckley and Bassett 1987b; Klimisch 1993; Oldiges and Glaser 1986; Oldiges et al. 1989; Rusch et al. 1986). Smokers inhale cadmium, but studies of cadmium exposure in the general population are considered in Section 3.2.2 because the primary route of exposure for the general population is through the diet. Also, the many other toxic compounds in cigarette smoke make it difficult to attribute specific adverse effects of smoking to the inhalation of cadmium. 3.2.1.1 Death Numerous studies have shown that acute inhalation exposure to cadmium can cause death in humans and animals. In humans, several fatal inhalation exposures have occurred in occupational accidents. During the acute exposure, the general symptoms are relatively mild but, within a few days following exposure, severe pulmonary edema and chemical pneumonitis develop, leading to death due to respiratory failure (Beton et al. 1966; Lucas et al. 1980; Patwardhan and Finckh 1976; Seidal et al. 1993). The cadmium concentration in air was not measured in these cases of accidental death in humans. However, the lung concentrations of cadmium in the men who died from these accidental acute exposures were measured. In micrograms of cadmium per gram wet weight (w/w) of lung tissue (μg/g), Patwardhan and Finckh (1976) reported 1.5 μg/g, Beton et al. (1966) reported 2.5 μg/g, Barrett et al. (1947) reported 3.5 μg/g, and Lucas et al. (1980) reported 4.7 μg/g. Based upon estimates of the percentage of inhaled cadmium fume CADMIUM 48 3. HEALTH EFFECTS that would be retained in the lungs, Barrett et al. (1947) calculated an exposure of 2,500 minutes x mg/m3 in air would be fatal to humans. Beton et al. (1966) used a similar technique to estimate that an exposure to cadmium oxide in air of 8.63 mg/m3 for 5 hours led to the fatal deaths of the five workers with cadmium lung burdens of 2.5 μg/g. The lower lung concentrations reported by Patwardhan and Finckh (1976) prompted Elinder (1986b) to estimate that an exposure of 1–5 mg/m3 for 8 hours could be immediately dangerous. These estimates of air concentrations, however, are based on a number of uncertain assumptions concerning the duration of exposure and the retention of cadmium in the human lung being similar to that found in animal studies (Barrett et al. 1947; Elinder 1986b). No studies on deaths in humans from intermediate inhalation exposures were found. In a study on chronic exposures, Friberg (1950) attributes the deaths of 2 workers to exposure to cadmium dust in the air averaging 6.8 mg Cd/m3 (range 3–15 mg/m3). One worker was 57 years old at death (after 14 years of exposure to the dust) and the other was 60 years old at death (after 25 years of exposure to the dust). A detailed postmortem evaluation for the 60-year-old worker showed the presence of emphysema and the occurrence of hyaline casts in renal tubules, as well as slight nephrotic changes. Pneumonia was the direct cause of death as an acute complication of chronic bronchitis and pulmonary emphysema.