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In this review, we critically evaluated the epidemiological and toxicological evidence for the role of specific transition metals (As. Cr. Cu. Fe. Mn. Ni. Sc. Ti. V and Zn) in causing or contributing to the respiratory and cardiovascular health effects associated with ambient PM. Although the epidemiologic studies arc suggestive. and both the in vivo and in vitro laboratory studies document the toxicity of specific metals (Fe. Ni. V and Zn). the overall weight of evidence does not convincingly implicate metals as major contributors to health effects. None of the epidemiology studies that we reviewed conclusively implicated specific transition metals as having caused the respiratory and cardiovascular effects associated with ambient levels of PM. However, the studies reviewed tended to be internal ly consistent in identifying some metals (Fe, Ni, V and Zn) more frequently than others (As, Cu, Mn and Sc) as having positive associations wi th health effects. The major problem wi th which the epidemiological studies were faced was classifying and quantifying exposure. Community and population exposures to metals or other components of ambient PM were inferred from centrally- located samplers that may not accurately represent individual level exposures. Only a few authors reported findings that did not support the stated premise of the study; indeed, statistic ally significant associations are not necessarily biologically significant. It is likely that ·'negative studies" are under-represented in the published literature, making it a challenge to achieve a balanced evaluation of the role of metals in causing health effects associated with ambient PM. Both the in vivo and in vitro study results demonstrated that individual metals (Cu. Fe. Ni. V and Zn) and extracts of metals from ambient PM sources can produce acute inflammatory responses. However. the doses administered to laboratory animals were many orders of magnitude greater than what humans experience from breathing ambient air. The studies that used intratracheal instillation have the advantage of delivering a known dose to a specific anatomical location. but arc not analogous to an inhaled dose that is distributed over the surface area of the respiratory tract. Studies. in which laboratory animals or human volunteers inhaled CAPs best represent exposures to the general human population. The in vivo and in vitro studies reviewed provide indications that the probable mechanisms involved in the respiratory and cardiac effects from high metal exposures include: an inflammatory response mediated by formation of ROS, upregulation of genes coding for inflammatory cytokines, altered expression of genes involved in cell signaling pathways and maintenance of metals homeostasis.The fact that doses of metals many orders of magnitude greater than those existing in ambient air were required to produce measurable adverse effects in animals makes it doubtful that metals play any major role in respiratory and cardiovascular effects produced from human exposure to ambient PM. We...

Polycyclic aromatic hydrocarbons (PAH) and N-heterocyclic aromatic hydrocarbons (NHA) are environmental pollutants formed during the incomplete combustion of organic materials. Benzo(a)pyrene (BaP) and 7H-dibenzo(c,g)carbazole (DBC) are well-characterized representatives of the PAH and NHA classes of compunds, respectively. Both are demonstrated carcinogens that frequently co-occur in environmental mixtures. This preliminary study was conducted to investigate the effects of a binary mixture of BaP and DBC on lung carcinogenicity in the strain A/J mouse as manifested by tumor development and mutations in the K-ras gene. Male A/J mice were administered the following single intraperitoneal dose (mg/kg) combinations of BaP and DBC dissolved in a 0.2-mL volume of tricaprylin--10 DBC:10 BaP; 2 DBC:10 BaP; 2 DBC:100 BaP; and 10 DBC: 100 BaP, and each of the compounds alone at the same doses. Mice were sacrificed 8 months after carcinogen treatment and lung tumor multiplicity and K-ras mutations determined (high-dose combination). The combination of DBC and BaP produced fewer tumors than the sum of all tumors produced by each compound acting alone. The frequency of tumors with K-ras mutations was also less in a sample of the 10 DBC:100 BaP treatment group than in the same-dose, single compound-treated animals. The dominant mutations produced by BaP and DBC were expressed in tumors from animals treated with the mixture.