Lars Hagmar

IPCS guidelines for the monitoring of genotoxic effects of carcinogens in humans

The purpose of these guidelines is to provide concise guidance on the planning, performing and interpretation of studies to monitor groups or individuals exposed to genotoxic agents. Most human carcinogens are genotoxic but not all genotoxic agents have been shown to be carcinogenic in humans. Although the main interest in these studies is due to the association of genotoxicity with carcinogenicity, there is also an inherent interest in monitoring human genotoxicity independently of cancer as an endpoint. The most often studied genotoxicity endpoints have been selected for inclusion in this document and they are structural and numerical chromosomal aberrations assessed using cytogenetic methods (classical chromosomal aberration analysis (CA), fluorescence in situ hybridisation (FISH), micronuclei (MN)); DNA damage (adducts, strand breaks, crosslinking, alkali-labile sites) assessed using bio-chemical/electrophoretic assays or sister chromatid exchanges (SCE); protein adducts; and hypoxanthine-guanine phosphoribosyltransferase (HPRT) mutations. The document does not consider germ cells or gene mutation assays other than HPRT or markers of oxidative stress, which have been applied on a more limited scale.

Increased cerebrovascular mortality in patients with hypopituitarism

OBJECTIVE An increased prevalence of atherosclerosis has been shown among patients with hypopituitarism. The aim of the present study was to assess whether patients with hypopituitarism experience increased cardiovascular, in particular cerebrovascular, mortality.

Functional aspects of developmental toxicity of polyhalogenated aromatic hydrocarbons in experimental animals and human infants

A scientific evaluation was made of functional aspects of developmental toxicity of polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) in experimental animals and in human infants. Persistent neurobehavioral, reproductive and endocrine alterations were observed in experimental animals, following in utero and lactational exposure to PCBs, PCDDs and PCDFs. The lowest observable adverse effect levels (LOAELs) for developmental neurobehavioral and reproduction endpoints, based on body burden of TCDD-toxic equivalents (TEQs) in animals, are within the range of current background human body burdens. Relatively subtle adverse effects on neurobehavioral development and thyroid hormone alterations have also been observed in infants and children exposed to background levels. Exclusive use of the toxic equivalency factor (TEF) approach may underestimate the risk of neurodevelopmental effects, because both Ah receptor dependent and independent mechanisms may be involved in these effects. The use of marker congeners and/or bioassays based on Ah receptor mediated mechanisms are rapid, low cost pre-screening alternatives for expensive and time consuming gas chromatographic-mass spectrometric analysis.

Exposure to polybrominated diphenyl ethers and tetrabromobisphenol A among computer technicians.

This study investigates exposure to polybrominated diphenyl ethers (PBDEs) and tetrabromobisphenol A (TBBPA), which are used as flame retardants in electronic equipment, in a group of technicians with intense computer work. Thirteen PBDE congeners and TBBPA were quantified in serum from 19 computer technicians. Previously investigated groups of hospital cleaners with no computer experience, and clerks working full-time at computer screens were used for comparison. The computer technicians had serum concentrations of BDE-153, BDE-183 and BDE-209 that were five times higher than those reported among hospital cleaners and computer clerks. The median levels observed among the computer technicians were 4.1, 1.3, and 1.6 pmol/g lipid weight, respectively. In contrast, for BDE-47 there was no difference between the computer technicians and the others. BDE-100, BDE-203, and three structurally unidentified octa-BDEs and three nona-BDEs, were present in almost all samples from the computer technicians. Further, TBBPA was detected in 8 out of 10 samples. The levels of BDE-153, BDE-183, and one of the octa-BDEs were positively correlated with duration of computer work among technicians. On a group level an exposure gradient was observed, from the least exposed cleaners to the clerks, and to the highest exposed group of computer technicians. A dose (duration of computer work)-response relationship among computer technicians was demonstrated for some higher brominated PBDE congeners. Thus, it is evident that PBDEs used in computers and electronics, including the fully brominated BDE-209, contaminate the work environment and accumulate in the workers tissues.

Apparent Half-Lives of Hepta- to Decabrominated Diphenyl Ethers in Human Serum as Determined in Occupationally Exposed Workers

The aim of the present study was to model apparent serum half-lives of polybrominated diphenyl ethers (PBDEs) with 7–10 bromine substituents. Workers with occupational exposure to PBDEs have elevated serum levels of PBDEs, but these substances are also found in the general population and are ubiquitous environmental contaminants. The calculations were based on exposure assessments of rubber workers (manufactured flame-retarded rubber compound) and electronics dismantlers who donated blood during a period with no work-related exposures to PBDEs, and referents without any known occupational exposure (clerks, cleaners, and abattoir workers). The workers had previously been found to have elevated levels of high- and medium-brominated diphenyl ethers compared with the referent populations. We performed nonlinear mixed-effects modeling of kinetics, using data from previous and present chemical analyses. The calculated apparent half-life for decabromodiphenyl ether (BDE-209) was 15 days (95% confidence interval, 11–18 days). The three nona-BDEs and four octa-BDE congeners were found to have half-lives of 18–39 and 37–91 days, respectively. BDE-209 has a short half-life in human blood. Because BDE-209 is commonly present in humans in general, the results of this study imply that humans must be more or less continuously exposed to BDE-209 to sustain the serum concentrations observed. BDE-209 is more readily transformed and/or eliminated than are lower brominated diphenyl ether congeners, and human health risk must be assessed accordingly.

Urinary phthalate metabolites and biomarkers of reproductive function in young men.

Background: High exposure to phthalates, which are ubiquitous contaminants, has been shown in animal studies to produce detrimental effects on male reproductive functions. A recent study in humans reported dose–response relations between low phthalate levels in urine and human semen parameters, which raises the question whether humans are more sensitive to phthalate exposure than animals. Methods: Urine, serum, and semen samples were collected from 234 young Swedish men at the time of their medical conscript examination. Semen volume, sperm concentration, and motility were measured, together with sperm chromatin integrity (sperm chromatin structure assay) and biochemical markers of epididymal and prostatic function. We analyzed reproductive hormones in serum, and mono ethyl phthalate (MEP), mono ethylhexyl phthaltale (MEHP), mono benzyl phthalate (MBzP), mono butyl phthalate (MBP), and phthalic acid in urine. Results: For MBP, MBzP, and MEHP, no clear pattern of associations were observed with any of the reproductive biomarkers. Subjects within the highest quartile for MEP had fewer motile sperm (mean difference = 8.8%; 95% confidence interval = 0.8–17), more immotile sperms (8.9%; 0.3–18), and lower luteinizing hormone values (0.7 IU/L; 0.1–1.2), but there was no suggestion of harmful effects for most other endpoints. Phthalic acid actually was associated with improved function, as measured by several markers. Conclusions: The observed weak associations between 1 phthalate biomarker and impairment of a few aspects of reproductive function biomarkers were not consistent with results from a recent U.S. study. It is not yet possible to conclude whether phthalate exposure may reflect a hazard for human male reproduction.

Impact of Types of Lymphocyte Chromosomal Aberrations on Human Cancer Risk: Results from Nordic and Italian Cohorts

The frequency of cells with structural chromosomal aberrations (CAs) in peripheral blood lymphocytes is the first genotoxicity biomarker that has shown an association with cancer risk. CAs are usually divided into chromosome-type (CSAs) and chromatid-type aberrations (CTAs), with different mechanisms of formation. From a mechanistic point of view, it is of interest to clarify whether the cancer predictivity of CAs is different with respect to CSAs and CTAs. We report here cancer risk for cytogenetically tested, healthy subjects with respect to frequency of CAs, CSAs, and CTAs in peripheral blood lymphocytes, using Nordic (1981 subjects with CA data, 1871 subjects with CSA/CTA data) and Italian (1573 subjects with CA data, 877 subjects with CTA/CSA data) cohorts, with a median follow-up of 17 years. High levels of CAs at test were clearly associated with increased total cancer incidence in the Nordic cohorts and increased total cancer mortality in the Italian cohort. In the Nordic cohorts, significantly elevated cancer risks were observed for subjects with both high CSAs and high CTAs at test, and these variables showed equally strong cancer predictivity. The results of the Italian cohort did not indicate any clear-cut difference in cancer predictivity between the CSA and CTA biomarkers. There was no significant effect modification by age at test, gender, country, or time since test. The results suggest that both DNA double-strand breaks and other initial DNA lesions responsible for CSAs and CTAs are associated with cancer risk.

Parameters of immunological competence in subjects with high consumption of fish contaminated with persistent organochlorine compounds

SummaryConsumption of fatty fish species, like salmon and herring, from the Baltic Sea is an important source of human exposure to persistent organochlorine compounds, e.g. polychlorinated dioxins (PCDDs), dibenzofurans (PCDFs) and biphenyls (PCBs). Many of these compounds show immunotoxic and hepatotoxic effects in animals. We have now studied immunological competence, including lymphocyte subsets, in 23 males with a high consumption of fish from the Baltic Sea and in a control group of 20 males with virtually no fish consumption. The high consumers had lower proportions and numbers of natural killer (NK) cells, identified by the CD 56 marker, in peripheral blood than the non-consumers. Weekly intake of fatty fish correlated negatively with proportions of NK cells (rs = −0.32, P = 0.04). There were also, in a sub-sample of 11 subjects, significant negative correlations between numbers of NK cells and blood levels of a toxic non-ortho-PCB congener (IUPAC 126; rs = −0.68, P = 0.02) and a mono-ortho congener (IUPAC 118; rs = −.76, P = 0.01). A similar correlation, in 12 subjects, was seen for p,p′-DDT (rs = −0.76, P = 0.01). The corresponding negative correlation, in 13 subjects, with blood levels of PCDD/Fs was not significant (rs = −0.57, P = 0.07). No significant association was seen between organic mercury in erythrocytes and NK cells. Fish consumption was not associated with levels of any other lymphocyte subset. Neither were there any correlations with plasma immunoglobulins or liver enzyme activities. Our study indicates that accumulation of persistent organochlorine compounds in high consumers of fatty fish may adversely affect NK cell levels.

Polychlorinated biphenyls and thyroid status in humans: a review.

Animal studies show that exposure to polychlorinated biphenyls (PCBs) or other persistent organochlorine compounds can disrupt thyroid hormone homeostasis. In some reports dietary exposures to PCBs have also been claimed to affect circulating levels of thyroid hormones and thyrotropin (TSH) in humans. The aim of the present study was to review available epidemiologic studies within this field. A total of 13 studies fulfilled the inclusion criteria for the review. The overall impression is a lack of consistency between studies of reported correlations, neither are there any obvious interstudy dose-response associations. Thus, it cannot presently be concluded that PCB exposure has been convincingly shown to affect thyroid hormone homeostasis in humans. On the other hand, available data do not exclude such associations. It is important to be aware of the intrinsic limitations of the cross-sectional epidemiologic studies used.

Semen Quality and Exposure to Persistent Organochlorine Pollutants

Background: Inconsistent results have been found in previous human studies on male reproductive toxicity of persistent organochlorine pollutants. The majority of studies have been conducted among selected populations of infertility clients or among occupational cohorts including a limited number of participants. Methods: We conducted a cross-sectional study of semen quality and serum concentration of 2,2′,4,4′,5,5′-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (p,p′-DDE) among 763 men. We included men from all regions in Greenland (n = 194), fishermen from Sweden (n = 185), inhabitants of the city of Kharkiv, Ukraine (n = 195), and inhabitants of the city of Warsaw, Poland (n = 189). Blood samples were analyzed for CB-153 and p,p′-DDE using gas chromatography–mass spectrometry and adjusted for serum lipids. Results: Sperm concentration was not impaired with increasing serum CB-153 or p,p′-DDE levels in any of the separate groups or overall. Similarly, the proportion of morphologically normal sperm was not associated with either CB-153 or p,p′-DDE blood concentration. However, sperm motility was inversely related to CB-153 concentration in Greenland and the Swedish fishermen population. Across all 4 regions, the sperm motility decreased on average by 3.6% (95% confidence interval = 1.7% to 5.6%) per one-unit increase in the log of blood CB-153 (ng/g lipid). The concentration of p,p′-DDE was negatively associated with sperm motility in the Greenlandic population and in the compiled dataset. Conclusion: Adult exposure to persistent organochlorine pollutants within the ranges observed in the present study is not likely to cause reduction in sperm concentration or morphology. However, higher exposure may be associated with impaired sperm motility.