Assessment of Potential Toxicological Interactions after Combined Exposure to Cadmium and Lead in Workers

Adolf Vyskocil and Claude Viau

CEJOEM 2007, Vol.13. No.2.: 107–113

Workers are commonly simultaneously exposed to multiple chemical agents. Simultaneous exposure to lead and cadmium is highly probable in mining and smelting operations. Compounds of both metals are present in paints, solder, storage batteries, ceramics, glazing material. It is important to determine if the effects of specific compounds on biological functions are modified by the concomitant exposure to other compounds. Lead and cadmium exert toxic effects on hematopoietic, cardiovascular, reproductive and nervous systems in addition to causing lesions in the liver and kidneys.
     The central question involves the nature of the possible interactions between these contaminants and their consequences on the toxicity of a mixture. Is the toxicity simply the sum of the toxic effects of the individual substances at the same level of exposure? Or do the substances in the mixture interact supra-additively, thus producing an effect greater than the sum of the effects of the individual substances? Or does the interaction lead to a reduction in the effects of each of the components in the mixture, producing an antagonistic situation (infra-additivity)?
     Regulations and common industrial practices address the question of interactions by hypothesizing, by default, that toxic effects on common target organs are additive. The Quebec “Regulation Respecting Occupational Health end Safety” (RROHS) similarly to the ACGIH^® approach prescribes that “where two or more substances are present in the work location and where they have similar effects on the same organs of the human body, the effects of these substances are considered to be additive, unless it is established otherwise”. In some cases, this hypothesis may lead to an underestimation or an overestimation of the actual risk.
     The aim of this study was the evaluation of toxicological studies allowing the identification of possible additive or other interactive effects in mixtures of cadmium and lead in work environments.

Information was taken from primary references available in databases up to July 2007. We utilized the databases MixTox, POLTOX and TOXLINE. We also consulted the toxicological on line database developed and maintained by the Quebec Occupational Health and Safety Commission CSST.
     The interactions were evaluated only for realistic exposure concentrations in workplaces based on the permissible exposure limit values. In Quebec, the time-weighed average exposure value (TWAEV- the average concentration of a given chemical to which workers can be exposed for normal 8-hour workdays, 5 days a week) is 0.025 and 0.05 mg/m³ for cadmium and lead, respectively, including oxides and salts. These concentrations correspond to permissible daily doses of 0.0036 and 0.0071 mg/kg/d, respectively, using default worker’s lung ventilation of 10 m³/workshift and body weight of 70 kg.
     In humans, the toxicological data were evaluated only for exposure concentrations/doses up to 5 times the TWAEV. This factor was chosen because, according to the RROHS, “none of the excursions in exposure levels may exceed 5 times the time-weighted average exposure value during any length of time whatsoever”. Animal data were used when no human data were available. In this case, the data were evaluated only for exposure concentrations up to 100 times the TWAEV [factor of 10 for extrapolation of the LOAEL (lowest observed adverse effect level) towards the NOAEL (no observed adverse effect level) and 10 for the differences between species]. In some cases, the ACGIH TLV^® Committee uses these uncertainty factors to establish the “Threshold Limit Value” (TLV^®) from animal data, when there are no satisfactory human data available, and Quebec regulation is largely based on ACGIH recommendations.
     Doses/concentrations of lead or cadmium reported in various studies were converted to daily doses in mg/kg body weight/d using EPA Documentation of Biological Values for Use in Risk Assessment and the ratio of administered dose to permissible limit dose was calculated.

After screening exposure concentrations/doses, six studies were retained (Table 1). Chronically feeding rats with either cadmium or lead can induce a significant increase in systolic pressure. Perry et al. and Perry and Erlanger exposed female rats to 0.1, 1 and 5 ppm lead and/or cadmium in drinking water for up to 6 months. Administering both metals together usually doubled the increase of systolic pressure observed with either metal alone. In one experiment, the effect was supra-additive after 3 months of exposure to 1 ppm lead and cadmium producing an average increase of 43 mm Hg in systolic pressure. The average systolic pressures of 103, 115, 116 and 146 mm Hg were observed in controls and after exposure to lead, cadmium and the combination of both metals, respectively. These studies clearly indicate at least an additive effect for the mixture of lead and cadmium.

     In another study from the same laboratory Perry et al. exposed female rats to 1 ppm cadmium or 1 ppm cadmium plus 1 ppm lead in drinking water for 20 months. Exposure to the combination of lead and cadmium initially produced higher systolic pressures than cadmium alone (117 vs 109 mm Hg after 8 months), but this difference disappeared in middle age (124 vs 125 mm Hg after 16 months) and was reversed in old age (125 vs 132 mm Hg after 20 months). This trend reproduces prior observations that the initially significant effect of lead alone diminished with continued exposure and eventually became insignificant. This study does not allow to draw a conclusion on a possible interactive or additive effects as the authors did not expose the rats to lead only.
     Der et al. injected Sprague Dawley male rats daily with 0.050 and 0.250 mg of lead (as lead acetate) or cadmium (as cadmium chloride) or with 0.025 mg of both lead and cadmium for 70 days. Lead acetate was administered intraperitoneally and cadmium chloride intramuscularly. No effects were found on weight of testes, liver, adrenals, kidney, spleen or prostate after combined exposure. In animals treated with lead and cadmium alone, no pathological or histological changes were noted in the testes, prostate, epididymis or seminal vesicle. Authors declared that “testes histology of a group with simultaneous administration of the two metals showed an absence of spermatogenesis in some seminiferous tubules and an increase in the size of seminiferous tubules with large vacuoles in the centre indicating that low levels of lead and cadmium administered together have more synergic damaging effect on testes than higher levels of lead or cadmium alone” without any clear demonstration of the effects on the rats treated with either metals alone. This study does not allow to conclude on a possible interactive or additive effects as the individual doses were different from combined doses.
     Fortoul et al. studied the effects of inhalation of lead and cadmium alone and in mixture on mouse bronchiolar ultrastructure. CD1 adult male mice inhaled nebulized 0.01 M lead acetate and 0.006 M cadmium chloride alone or in combination for 1 h twice a week for 8 weeks. Average concentrations of Cd and Pb in the inhalation chamber were 27.1 and 6.6 µg/m³, respectively, during individual inhalation and only 13.2 and 2.4 µg/m³ during simultaneous inhalation. Morphological changes in the bronchiole were mainly observed in the mixture, with a decreased number of nonciliated bronchiolar cells and an increased number of bundles of dividing cells. Additive effect of Pb and Cd was suggested by the authors. However, combined exposure at a concentration that was lower than the individual exposures produces effect on bundles that was much higher than predicted if the effects were purely additive. It should therefore be considered that combined exposure to Pb and Cd leads to supraadditive effects on this parameter. So this study does not allow drawing a final conclusion on interactive or additive effects in bronchiolar epithelium as the individual doses were different from combined doses but it suggests minimally an additive effect.
     The effects of lead and cadmium on the hypothalamic-pituitary axis was studied in proestrous rats by Pillai et al.. Adult female rats were treated intraperitoneally with either lead acetate and cadmium acetate alone or in combination at a dose of 0.05 mg/kg daily for 15 days. Hypothalamic serotonin (5-HT), dopamine (DA) and norepinephrine (NE) and plasma and pituitary levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH) were measured. 5-HT and NE levels decreased in individually and combined metal treated groups whereas DA levels were decreased only in Cd-exposed group. The pituitary levels of LH and FSH were decreased significantly in Cd and combined treatment groups. Lead exposure failed to cause any changes in serum LH and FSH levels, whereas Cd and combined treatments showed significant decrease in serum LH and FSH levels. According to the authors, the hormonal disturbances following combined treatment with lead and cadmium more often paralleled the effects of cadmium alone than the changes seen in lead alone. It is clear that the effects produced by the combined treatment with Cd and Pb on the hypothalamic-pituitary axis are not additive.

It is evident that combined exposure to lead and cadmium in mammalian biological systems alter effects produced by the individual metals. Cadmium and lead were suggested as a possible cause of human hypertension. However, unlike the cadmium effect, the lead effect seemed to decrease with time. Studies by Perry et al. and Perry and Erlanger on rats clearly indicate an additive effect for the mixture of lead and cadmium. The study of Der et al. on reproduction in male rats is not convincing. The study of Fortoul et al. suggests supraadditive effect in the bronchiolar epithelium. Finally, the study of Pillai et al. shows no interactive effects in the hypothalamic-pituitary axis.
     The applicability of these results to man remains to be proven but reported effects resulted from realistic doses of lead and cadmium in comparison to occupation doses. In conclusion, based on the studies of Perry et al., Perry and Erlanger and Fortoul et al., we recommend to consider at least an additive effect for the mixture of cadmium and lead.

This study was supported by the Institut de recherche Robert-Sauvé en santé et en sécurité du travail (Quebec, Canada). We are grateful to Mrs. F. Gagnon for skilful technical assistance.