Cadmium exposure and tobacco consumption: Biomarkers and risk assessment

Abstract

To investigate whether cadmium has an independent role in diseases associated with tobacco consumption, epidemiology data were reviewed, biomonitoring data were analyzed, and probabilistic risk assessment (PRA) was performed. Results from previous epidemiology studies have indicated that there are adverse health effects potentially in common between cadmium exposure and tobacco consumption. Analysis of publically available biomonitoring data showed that blood (B–Cd) and urine (U–Cd) cadmium were higher in cigarette smokers compared with smokeless tobacco (SLT) consumers, and B–Cd and U–Cd in SLT consumers were not significantly different than in non-consumers of tobacco. Comparison with previously established biomonitoring equivalent (BE) values indicated that B–Cd and U–Cd in the majority of these cigarette smokers and SLT consumers did not exceed the blood and urine BEs. Results of the PRA showed that the mean hazard estimate was below a generally accepted regulatory threshold for SLT consumers, but not for cigarette smokers. In total, this evaluation indicated that cadmium exposures in tobacco consumers differed by product category consumed; cadmium in tobacco may not be associated with tobacco consumption related diseases; if cadmium in tobacco contributes to tobacco consumption related diseases, differences in hazard and/or risk may exist by product category.

Introduction

Soil cadmium concentrations vary throughout the tobacco growing regions of the world. Major sources of soil cadmium contamination include natural environmental processes (e.g., volcanic activity) (WHO, 1992a, WHO, 1992b), emissions from the nonferrous metals industry (Nriagu and Pacyna, 1988), and agricultural application of sewage sludge and phosphate fertilizers (WHO, 1992a, WHO, 1992b). The tobacco plant can accumulate cadmium, with uptake into the roots and leaves primarily influenced by tobacco species and soil characteristics (Järup and Akesson, 2009, Wagner and Yeargan, 1986, Westcott and Spincer, 1974, WHO, 1992a, WHO, 1992b). Accordingly, cadmium is measurable in tobacco and in cigarette mainstream smoke (MSS). Cadmium concentration in both non-combusted and combusted tobacco products varies with global sources of tobacco, and cadmium concentration in cigarette MSS may also vary with cigarette physical design parameters such as ventilation and filtration (Bache et al., 1987, Figueres and de Salles de Hys, 1994, Kalaitzoglou and Samara, 1999, Perinelli and Carugno, 1978). In certain smokeless tobacco (SLT) products, cadmium concentrations have been reported to range between 450 and 1880 ng per gram dry weight (Hoffmann et al., 1987, Maier et al., 1989, Pappas et al., 2008). In non-combusted cigarette tobacco, cadmium has been reported at concentrations between 100 and 4,950 ng per gram of tobacco (Viana et al., 2011, Westcott and Spincer, 1974, Yue, 1992). And in cigarette MSS, depending on cigarette design and the machine smoking regimen, cadmium concentrations between 1.6 and 222 ng per cigarette have been reported (Counts et al., 2005, IARC, 2004). MSS cadmium levels in counterfeit cigarettes have been reported to be 2–7 times higher than authentic cigarette brands (Pappas et al., 2007). Actual human exposure to cadmium from consumption of tobacco products may vary with product category (i.e., combustible vs. non-combustible products), as well as with duration, intensity, and frequency of product consumption.

Biomarkers of cadmium exposure, including blood and urine cadmium (B–Cd and U–Cd, respectively) are established. Typically, B–Cd is considered related to recent cadmium exposure (Hays et al., 2008a, Järup and Akesson, 2009). U–Cd is considered to be a relevant marker of chronic cadmium exposure as well as renal concentrations of cadmium. The kidney is deemed the critical organ for cadmium toxicity in humans. A widely accepted indicator of kidney damage is the increased excretion of low molecular weight proteins (i.e., proteinuria) (Järup and Akesson, 2009), indicating kidney effects preceding kidney damage. The concentration of cadmium in the cortex of the kidney has been identified as the dose metric most often associated with cadmium-induced proteinuria (Hays et al., 2008a), and thus cadmium non-cancer risk assessments rely on estimates of internal dose (i.e., U–Cd or renal cortex cadmium concentration) from human populations for the determination of acceptable cadmium exposure levels. As U–Cd concentrations are most closely associated with the concentration of cadmium in the renal cortex, U–Cd concentration is useful as a surrogate for the dose metric associated with the critical toxic response. Cadmium exposure is also associated with bone and respiratory damage in humans and is considered a known (IARC, 2012) or probable (USEPA, 1992) human carcinogen, with the lung as the specified target organ. U–Cd was associated with cancer mortality in men and women in a recently published study in the United States (US) (Adams et al., 2012). Other systems possibly affected by cadmium exposure are cardiovascular, immunological, hematopoietic, and hepatic (Järup and Akesson, 2009, Fowler, 2009). As noted, however, the kidney is identified as the most sensitive target in humans, and for risk assessment, most non-cancer exposure guidance values for cadmium are based on protection against cadmium-induced kidney damage.

Despite the chemical and physical complexity of cigarette MSS and the inter-and intra-variability in human cigarette smoking behavior, it has been suggested that it may be possible to reduce cigarette MSS toxicity by reduction of constituents most likely to be associated with cigarette smoking-related disease. For example, the World Health Organization (WHO) Framework Convention on Tobacco Control (FCTC) has included cadmium on the list of cigarette MSS constituents of “high priority for disclosure and monitoring of their levels by brand”, although cadmium is not currently recommended by the FCTC for mandatory lowering (Burns et al., 2008). Additionally, an analysis by Cox (2006) concluded, based on potential mechanisms of cadmium carcinogenicity, that removing cadmium from cigarette MSS may result in a significantly decreased risk of smoking-related lung cancer. Draft guidance issued by the US Food and Drug Administration identified cadmium on the abbreviated list of harmful and potentially harmful constituents in roll-your-own tobacco and cigarette filler as well as SLT (USDHHS, 2012).

In an attempt to investigate if cadmium is independently associated with tobacco consumption related adverse health outcomes in tobacco consumers, this study estimated and compared U–Cd and B–Cd in cigarette smokers, SLT consumers, and non-consumers of tobacco using publically available survey data representative of the US population. Estimated U–Cd and B–Cd values were then compared with (1) biological cadmium concentrations associated with adverse health outcomes from previously published epidemiological studies and (2) established biomonitoring equivalent (BE) values for blood and urine (Hays et al., 2008a). A BE is “the concentration or range of concentrations of chemical in a biological medium (blood, urine, or other medium) that is consistent with an existing health-based exposure guideline.” (Hays et al., 2008a.) It has been suggested that the derivation and use of BEs may be useful for the interpretation of human biomonitoring data in the context of public health risk assessment (Hays et al., 2008a).

In addition, a probabilistic risk assessment (PRA), including incremental lifetime cancer risk (ILCR) and hazard quotient (HQ) calculations specific to cadmium exposures from cigarette smoking and SLT consumption, was performed. PRA is a scientific evidence based tool that can be used to estimate non-cancer hazard and cancer risk. In the application conducted and presented here, PRA incorporated the range of potential exposures to cadmium, as well as the range of human characteristics related to exposure to tobacco products. To varying degrees, similar methodologies have been used to estimate non-cancer hazards and cancer risks of chemicals in occupational and environmental settings (e.g., OSHA, 1992), as well as in cigarette MSS and SLT products (e.g., Ayo-Yusuf and Connolly, 2011, Fowles and Dybing, 2003).

With these tools, cadmium exposure from cigarette smoking and SLT consumption, as well as the potential association between cadmium exposure and tobacco consumption related diseases, was evaluated.