Armand Dhamo

Particulate matter, science and European Union policy

To the Editors: The editorial of Annesi-Maesano et al. 1 summarises current evidence concerning the adverse health effects of particulate matter (PM) and correctly outlines that: 1) the health effects of air pollution are a big problem worldwide; and 2) several scientific questions are still open. In addition, the authors press for more stringent measures of prevention, in order to achieve adequate protection of the exposed population. In particular, they outline that “experimental research has rapidly progressed” and only “details of the pathophysiological mechanisms remain to be elucidated”. We agree with most of their statements and are in favour of more stringent rules for the European Union (EU). However, we would like to make some comments concerning the open questions, in order to increase the scientific strength that should convince EU authorities. The World Health Organization estimates that inhalation of PM in ambient air causes 500,000 premature …

Adverse health effects from combustion-derived nanoparticles: the relative role of intrinsic particle toxicity and host response.

It is widely accepted that airborne pollution causes adverse health effects in humans (Gauderman et al. 2007). In addition to the concentration of particulate matter (PM), these effects have been related to innate particle toxicity. Stoeger et al. (2009) recently showed that, with a slope that significantly depends on particle structure, surface, and organic carbon content, combustion-derived nanoparticles behave in a different manner in in vitro systems and when reacting with lung surface (i.e. after particle–lung interaction). We have stressed that mechanistic linkages between PM and health effects should be investigated in more detail (Cetta et al. 2007, 2008). Here, we would like to comment on the role of the individual response in the occurrence of the clinically evident outcome, that is, how individual charac teris tics of the host, in the presence of the same (or similar) noxious agents, are responsible for or determine the type and the severity of the response. Until now, toxicity has been considered mainly as an intrinsic property of each pollutant, depending on size, type, and composition of each particle. Stoeger et al. (2009) focused specifically on structure, BET (Brunauer, Emmett, and Teller) surface area, and oxidative potency. Interestingly, they stressed particle–lung interaction and the ability of some particles rich in organic content, namely, soot with high organic content, to determine a higher than expected inflammatory response due to increased cytochrome P450 1A1 induction; they also introduced a new parameter, inflammatory efficacy, in addition to oxidative potency. In our opinion, this could be just the top of the iceberg. In fact, “oxidative stress” is a working hypothesis in the search for a common mechanistic linkage between particulate material and adverse health effects. But it is not unique. In particular, in a recent in vitro study in which different types of particles were used (PM < 2.5 or = 10 μm in aero dynamic diameter, tire debris), the same concentration of different particles with the same exposure time elicited different effects on sperm cell function (motility, viability, rate of apop-tosis) (Collodel G, Geminiani M, Cetta F, Camatini M, Bolzacchini E, Renieri T, unpublished data). However, variability of the observed effects was less than that elicited by changing the host, with lower adverse effects in New Zealand rabbit sperm, more evident effects in human sperm, and very severe effects in humans with previous impaired sperm function (e.g., varicocele). Sperm cell function is easy to quantify and compare not only among different pollutants but also among different host species or subgroups. These findings are in accordance with recent epidemiologic data showing more pronounced respiratory and cardiovascular effects in patients with previous respiratory and cardiovascular impairment or specific susceptibility, respectively (Gauderman et al. 2007). The results of these studies will also have relevant implications for policy makers (Cetta et al. 2007). In fact, until now, contrast measures have mainly been directed to reduce PM concentration. Curent evidence suggests that—more important than reducing the overall PM concentration—it is of paramount importance to reduce selectively the concentration of those pollutants that are more toxic or more strictly related with adverse health effects, such as traffic-related particles. In the future, because of the better knowledge of the host response and of the variability of individual susceptibility in the occurrence of these effects, a major goal for policy makers will be the proper and early recognition—by means of sensible and specific tests—of at-risk subpopulations. This early recognition of at-risk subpopulations could facilitate better prevention or reduction of negative effects of host–pollutant interactions.

Linking Environmental Particulate Matter with Genetic Alterations

In their article, Tarantini et al. (2009) focused on the basic question of mutual relationships between environmental and genetic factors. From a more general point of view, this also involves the question concerning the relative role of “intrinsic toxicity” of xenobiotics and individual susceptibility or host response. In particular, data from epidemiologic and in vitro studies must cope with pathologic evidence for pathologists, as well as cause-and effect-relationships for pathophysiologists. In between are inferences and extrapolations on the basis of plausibility. Tarantini et al. (2009) showed, for the first time in humans, that reactive oxygen species (ROS)—which are considered one of the main cellular stressors generated by PM exposure—may produce genomic hypomethylation and increased expression and activity of inducible nitric oxide synthase (iNOS) not only in vitro, but in humans exposed to particulate matter (PM). Although this finding is expected, it is a step forward, based on DNA adduct generation produced by polycyclic aromatic hydrocarbons (PAHs) and other PM components, namely transition metals. Alterations of DNA methylation of the promoter is a common finding in environmental-related chronic or cancerous diseases. Alterations in DNA methylation and iNOS methylation, as observed by Tarantini et al. (2009) in association with exposure to PM < 10 μm in aerodynamic diameter, may represent an initial step in reproducing decreases in global DNA methylation content that are eventually observed in cardiovascular diseases and cancer. However, pathologists and pathophysiologists are required to interpret more correctly what this means. Subjects with inherited multi tumoral syndromes have a germline mutation, usually a point mutation present in all cells of the body, which determines the occurrence of multiple tumors in the same individual. The occurrence of DNA adducts or mutations in some cells or tissues due to exposure to PAHs or diesel exhaust does not necessarily induce clinically evident outcomes in the future, because each individual is endowed with a wide variety of natural defenses and repair mechanisms that usually overcome every type of DNA damage. Therefore, the first inference to avoid is that DNA adduct formation or alterations in the promoter methylation of a gene causes cancer in the absence of inherited or acquired predisposition (i.e., a point germline mutation of a tumor suppressor gene or an acquired sporadic mutation). In addition, even in patients with inherited multitumoral syndromes (i.e., in subjects with germline mutations of suppressor genes), tumor occurrence (type and severity) is also greatly influenced by epigenetic factors, environmental stimuli, or even long-distance catastrophes. We previously demonstrated an increased incidence of papillary thyroid carcinoma in three members of the same familial adenomatous polyposis (FAP) family (i.e., a kindred having a 1061 APC gene mutation). This mutation is responsible for FAP, in part as a side effect (long-term–long-distance) after the Chernobyl disaster, thus suggesting a wider than expected impact of environmental disasters in predisposed subjects (Cetta et al. 1997, 2000). Analogously, chronic exposure to toxic or carcinogenic environmental substances does not elicit the same results in all individuals. The final clinical outcome (cancer, asthma, pulmonary fibrosis, atherosclerosis, or coronary diseases) seems to be less dependent on the toxic potency of the pollutant or of the exposure dose and more on the individual susceptibility of the host (Cetta 2009a, 2009b). This approach should facilitate a better understanding of the < 5% incidence of mesotheliomas in subjects with the same chronic exposure to asbestos, or the absence of health effects in husbands with chronic occupational exposure to asbestos but the occurrence of mesotheliomas in wives with minor indirect exposure from their husbands (Cetta F, unpublished data). However, acute and chronic inflammation is the first pathological step. The final clinical outcome (e.g. cancer) does not depend on the first DNA adduct formed or a genetic mutation produced by xenobiotics. A long, automaintaining process will start, such as in liver cirrhosis, leading to cancer or chronic alterations as the final result of the interactions between host and the pathogenic agent. This process is greatly influenced by individual susceptibility or resistance. In PM-related diseases, a major role—in addition to the intrinsic toxicity of the xenobiotic—is played by individual host susceptibility and reactivity, similar to what occurs in auto immune or autoinflammatory diseases.

Fewer infectious manifestations are induced by bacteria entrapped in cholesterol stones than by bacteria in brown pigment gallstone.

To the Editor. “Fewer infectious manifestations are induced by bacteria entrapped in cholesterol stones than by bacteria in brown pigment gallstones” comment concerning the articles by Stewart, et al: “Gallstones containing bacteria are biofilms. Bacterial slime production and ability to form pigment solids determines infection severity and bacteremia” J Gastrointest. Surg. 2007;11:977–984 and “Bacteria entombed in the center of cholesterol gallstones induce fewer infectious manifestations than bacteria in the matrix of pigment stone” J Gastrointest Surg; 2007;11:1298–308. We agree with many statements and conclusions of the papers by Stewart, et al. However, we would like to make some remarks and comments. In addition to outline that our comprehensive study (1,000 consecutive patients studied in 1991, more than 2,000 today) showed for the first time bacterial microcolonies in brown stones by SEM, we would stress the importance of considering brown stones, and only pure and entirely brown stones, as a different disease from other types of gallstones. In fact, only in these stones infection plays a basic role in stone formation from the beginning, being responsible for the precipitation of all stone components. Pure brown stones are mainly found as recurrent common duct stones after sphincterotomy and biliaryenteric anastomosis. Nowadays, these stones are usually removed by repeat endoscopic sphincterotomy. Therefore, pure brown stones are today seldom removed by surgery and are very rare in a consecutive surgical series of 250–350 patients. On the contrary, in our study dating back to 1970s and recruiting more than 2,000 consecutive patients, we could observe a lot of these stones showing bacteria both in the stone center and periphery. They were always associated with positive bileculture and frequently with severe infectious clinically evident complications. These stones must be classified as a different disease. Bacteria, or bacterial DNA can be found in bile and stones, and is increasingly detectable with improvement of diagnostic tools. However, these cholesterol, black, mixed or combination stones have a different pathogenesis from brown stones. Obviously, the more abundant the brown material, (which can precipitate in the periphery of a previous cholesterol stones or as entirely brown concrements associated with cholesterol or mixed stones in the same patient), the more severe are infectious complications. Stewart, et al. suggest that infectious complications are more related with phospholipase-beta glucuronidase activity and inversely related with slime production. This is a logical thing, which further improves our knowledge. But the better knowledge of these details, together with the improvement of diagnostic tools, cannot change our basic knowledge that only brown stones are “bacterial” stones, whereas all other stones form because of mechanisms different from infection. We would like to stress that diagnostic refinement and improvement of pathophysiological mechanisms should go to the right direction, i.e. not to change long established classification J Gastrointest Surg (2008) 12:988–990 DOI 10.1007/s11605-008-0466-2