Premature mortality and hypopituitarism.
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Cardiovascular Diseases↗
Biomedical subjects
L Hagmar
Publications and source records attributed to L Hagmar.
Plasma concentrations of persistent organochlorines in relation to thyrotropin and thyroid hormone levels in women.
OBJECTIVES: There is a concern that persistent organohalogen toxicants, such as polychlorinated biphenyls (PCBs), might display endocrine-disrupting effects in exposed populations. In this study the correlations between PCBs and thyrotropin (TSH) and thyroid hormone concentrations in plasma were assessed in adult women. METHODS: The study group consisted of 182 fishermen's wives from the Swedish east coast, with a median age of 42 years (range 23-62) and a median current consumption of contaminated fatty fish from the Baltic Sea of two meals per month (range 0-12). TSH, free (FT3) and total (TT3) triiodothyronine and free (FT4) and total (TT4) thyroxin in plasma were analyzed by immunofluorometric assays, and 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) in plasma was analyzed by gas chromatography with electron capture detection. Twenty other PCB and two hydroxy-PCB congeners were analyzed in subgroups of the women. Plasma lipid analyses were performed with enzymatic techniques. RESULTS: The CB-153 concentration in plasma (range 16-776 ng/g lipid) was negatively correlated with the TT3 concentrations (range 1.0-3.0 nmol/l, rs = -0.29, P < 0.001). This association remained after age adjustment. CONCLUSIONS: The present study gives some support for the notion that dietary exposure to persistent organochlorine compounds (POCs) might weakly affect peripheral thyroid hormone concentrations in adult women.
Adult↗
Smoking and acute myeloid leukemia: associations with morphology and karyotypic patterns and evaluation of dose-response relations.
This case-control study of tobacco smoking and acute myeloid leukemia (AML), emphasizing specific associations with morphologic and cytogenetic subtypes, comprised smoking histories for 333 cases and 351 controls. Smoking status (ever smokers versus life-long non-smokers) showed no evident effect on AML risk. However, an effect of smoking was indicated at high cumulative smoking doses (pack-years), e.g. 40 pack-years was associated with an odds ratio (OR) of 1.5 [95% confidence interval (CI) 1.0-2.3]. Among morphologic subtypes, the smoking associated OR for acute erythroleukemia was 8.9 (95% CI 1.0-76). No clear associations between smoking and cytogenetic subtypes of AML were observed.
Acute Disease↗
The prognostic impact of karyotypic subgroups in myelodysplastic syndromes is strongly modified by sex.
The prognostic impact of karyotypic patterns in a consecutive series of 389 adult myelodysplastic syndromes (MDS) was investigated. Time period did not significantly influence the survival times. In the analyses, the MDS cases were subdivided into the cytogenetic subgroups used in the International Prognostic Scoring System, i.e. favourable [-Y, del(5q) or del(20q) as single aberrations or normal karyotype, n = 241], poor [-7, del(7q), der(1;7) or complex karyotypes, i.e. > or = three abnormalities, n = 89] and intermediate (other aberrations, n = 59). The survival times correlated well with the prognostic subgroups, confirming that the cytogenetic classification was valid. Expressed as hazard ratios (HRs), with the favourable subgroup as the reference, the intermediate and poor subgroup HRs increased to 1.5 (95% confidence interval, 1.1-2.1) and 3.2 (2.4-4.1) respectively. Sex, age, morphological subtype and smoking habits significantly modified this prognostic impact. Shorter survival was detected for men in the favourable and the intermediate subgroups, but not in the poor prognosis subgroup. Using women in the favourable subgroup as the reference and adjusting for age, the HR for men was 1.6 (1.2-2.1) in the favourable subgroup. Adjusting for smoking habits as well decreased the HR to 1.4 (1.1-2.0) and, when also excluding cases with del(5q) as the sole anomaly, no significant difference could be discerned [HR 1.2 (0.9-1.6], suggesting that the better outcome for women in the favourable subgroup was mainly as a result of the '5q-syndrome' and to smoking habits. In the intermediate subgroup, the corresponding HRs were 3.0 (1.5-6.0) when adjusted for age and 2.7 (1.3-5.5) when also adjusted for smoking habits. Different survival times between men and women have never previously been reported for this MDS group. Although it remains to be elucidated whether environmental and/or constitutional factors cause the observed sex-related difference, these observations have obvious clinical ramifications, not least in designing and evaluating therapy protocols.
Adult↗
Is there an increase in second brain tumours after surgery and irradiation for a pituitary tumour?
OBJECTIVE: To assess the incidence of second brain tumours in patients operated and irradiated for pituitary tumours. DESIGN AND PATIENTS: The study base consisted of a consecutive series of 325 patients operated and irradiated for pituitary tumours, excluding patients with acromegaly and Cushing's disease. Comparison was made with the general population from the same catchment area as the patients. The follow-up period started in 1958 and on an individual basis patients were followed from the onset of postoperative irradiation until December 1995, or until date of death, emigration or a second brain tumour diagnosis, whichever occurred first. RESULTS: Three brain tumours (two astrocytomas and one meningioma) were observed, compared with 1-13 expected (standardized incidence ratios (SIR) 2.7; 95% confidence interval (CI) 0.6-7.8). CONCLUSION: The present study gives no firm support for an increased incidence of a second brain tumour in patients operated and irradiated for pituitary tumours. A crude meta-analysis of the present and previously published cohort studies of patients with irradiated pituitary tumours gives an SIR of 6.1 (95% CI 3.16-10.69). Thus, the results of the meta-analysis are in favour of an increased risk for second brain tumours. A genetic trait that predisposes to both pituitary tumours and brain tumours is an alternative causal factor. There is no definite proof that cranial irradiation per se is the causal factor. This question cannot be fully answered until sufficient cohort studies of nonirradiated pituitary tumour patients have been carried out.
Adult↗
The usefulness of cytogenetic biomarkers as intermediate endpoints in carcinogenesis.
During the last decades, cytogenetic biomarkers in peripheral lymphocytes have been used to assess exposure to carcinogenic or mutagenic agents in occupational settings. The first method in use assessed chromosomal aberrations (CA). It is generally accepted that chromosomal mutations are causal events in the development of neoplasia, and it has earlier been postulated, but not proven, that increased chromosomal damage may reflect an enhanced cancer risk. Two less laborious techniques, sister chromatoid exchanges (SCE) and micronuclei (MN), were introduced later-on in occupational health surveillances. SCE represent symmetrical exchanges between sister chromatids; generally they do not result in alteration of the chromosome morphology. MN represent small, additional nuclei formed by the exclusion of chromosome fragments or whole chromosomes lagging at mitosis. MN rates therefore indirectly reflect chromosome breakage or impairment of the mitotic apparatus. The health significance of increased levels of SCE and MN is poorly understood. The usefulness of these cytogenetic techniques for implementing preventive measures in the workplaces depend on how well they serve as biomarkers of exposure but also on whether they can predict cancer risk or not. Recently performed epidemiological studies show that the CA frequency predicts the overall cancer risk in healthy subjects. Such associations could not been seen for SCE or MN. Age, sex, or time since test did not affect the predictive value of CA. This predictivity was seen irrespective of whether the subjects had been smokers or occupationally exposed to carcinogenic agents. Risk factors such as age, smoking and occupational exposures usually explain only some of the interindividual variation in CA frequency. It seems reasonable that not yet identified individual susceptibility factors explain a large fraction of the interindividual CA variation and also the cancer predictivity of the CA biomarker.
Adult↗
Update of the follow-up of mortality and cancer incidence among European workers employed in the vinyl chloride industry.
Although vinyl chloride is an established cause of liver angiosarcoma, the evidence is inconclusive on whether it also causes other neoplastic and nonneoplastic chronic liver diseases as well as neoplasms in other organs. Furthermore, the shape of the dose-response relation for angiosarcoma is uncertain. We have extended for approximately 8 years the mortality and cancer incidence follow-up of 12,700 male workers in the vinyl chloride industry in four European countries. All-cause mortality was lower than expected, whereas cancer mortality was close to expected. A total of 53 deaths from primary liver cancer (standardized mortality ratio 2.40, 95% confidence interval = 1.80-3.14) and 18 incident cases of liver cancer were identified, including 37 angiosarcomas, 10 hepatocellular carcinomas, and 24 liver cancers of other and unknown histology. In Poisson regression analyses we observed a marked exposure response for all liver cancers, angiosarcoma, and hepatocellular carcinoma. The exposure-response trend estimated for liver cancer in analyses restricted to cohort members with cumulative exposures of <1,500 parts per million-years was close to that estimated for the full cohort (relative risk of 2.0 per logarithmic unit of cumulative dose). No strong relation was observed between cumulative vinyl chloride exposure and other cancers. Although cirrhosis mortality was decreased overall, there was a trend with cumulative exposure.
Carcinogens↗
Are occupational, hobby, or lifestyle exposures associated with Philadelphia chromosome positive chronic myeloid leukaemia?
OBJECTIVES: To investigate a broad range of occupational, hobby, and lifestyle exposures, suggested as risk factors for Philadelphia chromosome positive (Ph+) chronic myeloid leukaemia (CML). METHODS: A case-control study, comprising 255 Ph+CML patients from southern Sweden and matched controls, was conducted. Individual data on work tasks, hobbies, and lifestyle exposures were obtained by telephone interviews. Occupational hygienists assessed occupational and hobby exposures for each subject individually. Also, occupational titles were obtained from national registries, and group level exposure-that is, the exposure proportion for each occupational title-was assessed with a job exposure matrix. The effects of 11 exposures using individual data and two exposures using group data (organic solvents and animal dust) were estimated. RESULTS: For the individual data on organic solvents, an effect was found for moderate or high intensity of exposure (odds ratio (OR) 3.4, 95% confidence interval (95% CI) 1.1 to 11) and for long duration (15-20 years) of exposure (OR 2.1, 95% CI 1.1 to 4.0). By contrast, the group data showed no association (OR 0.69, 95% CI 0.27 to 1.8; moderate or high intensity versus no exposure). For extremely low frequency electromagnetic fields (EMFs), only individual data were available. An association with long occupational exposure to EMFs was found (OR 2.3, 95% CI 1.2 to 4.5). However, no effect of EMF intensity was indicated. No significant effects of benzene, gasoline or diesel, or tobacco smoking were found. OR estimates below unity were suggested for personal use of hair dye and for agricultural exposures. CONCLUSIONS: Associations between exposure to organic solvents and EMFs, and Ph+CML were indicated but were not entirely consistent.
Adult↗
Incidence of a second tumor in hypopituitary patients operated for pituitary tumors.
Recently, an association between increased blood levels of insulin-like growth factor I (IGF-I) and increased risks of prostate, breast, lung, and colorectal cancers has been suggested. As today adults with GH deficiency are subjected to GH substitution, there is a pressing need for baseline tumor incidence data. The aim of the study was to assess the risk for a second tumor in a cohort of 328 patients with hypopituitarism treated for a pituitary tumor from 1958--1992. The patients were receiving conventional hormone treatment, but without GH substitution. The overall tumor incidence [standardized incidence ratio (SIR)] was lower than expected (0.85), but the 95% confidence interval (CI) did not exclude unity (0.59--1.21). Only two prostate cancers occurred (SIR, 0.34; 95% CI, 0.04--1.24). Two brain tumors (SIR, 1.96; 95% CI, 0.24--7.08) and two endocrine tumors (part of multiple endocrine neoplasm syndromes; SIR, 4.00; 95% CI, 0.48--14.5) had occurred. When excluding brain and endocrine tumors, the overall SIR decreased to 0.77, but did still not differ significantly from unity (0.52--1.13). Thus, a tendency for a decreased overall tumor risk, although not statistically significant, was noted, especially when excluding brain and endocrine tumors. This tendency was more emphasized for prostate cancer, but low numbers hamper a firm conclusion. These results may serve as a baseline for tumor risk among adult patients with pituitary insufficiency supplemented with GH.
Adolescent↗
How confident can we be that acrylonitrile is not a human carcinogen?
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Acrylonitrile↗
Health effects of occupational exposure to acrylamide using hemoglobin adducts as biomarkers of internal dose.
OBJECTIVES: This study assessed the health effects of occupational acrylamide exposure using hemoglobin (Hb) adducts as biomarkers of internal dose. METHODS: Two hundred and ten tunnel workers exposed for about 2 months to a chemical-grouting agent containing acrylamide and N-methylolacrylamide underwent a health examination. Blood samples were drawn for the analysis of Hb adducts of acrylamide. Fifty workers claiming recently developed or deteriorated symptoms of the peripheral nervous system (PNS) were referred to a neurophysiological examination. Workers with Hb-adduct levels exceeding 0.3 nmol/g globin attended follow-up examinations 6, 12, and 18 months after exposure cessation. RESULTS: Forty-seven workers had Hb-adduct levels within the normal background range (0.02-0.07 nmol/g globin), while the remaining 163 had increased levels up to a maximum of 17.7 nmol/g globin. Clear-cut dose-response associations were found between the Hb-adduct levels and PNS symptoms. Thirty-nine percent of those with Hb-adduct levels exceeding 1 nmol/g globin experienced tingling or numbness in their hands or feet. A no-observed adverse effect level of 0.51 nmol/g globin was estimated for numbness or tingling in the feet or legs. For 23 workers there was strong evidence of PNS impairment due to occupational exposure to acrylamide. All but two had recovered 18 months after the cessation of exposure. CONCLUSIONS: Occupational exposure to a grouting agent containing acrylamide resulted in PNS symptoms and signs. The use of Hb adducts of acrylamide as a biomarker of internal dose revealed strong dose-response associations. The PNS symptoms were, however, generally mild, and in almost all cases they were reversible.
Acrylamide↗
Chromosomal aberrations in lymphocytes predict human cancer independently of exposure to carcinogens. European Study Group on Cytogenetic Biomarkers and Health.
An increased risk of cancer in healthy individuals with high levels of chromosomal aberrations (CAs) in peripheral blood lymphocytes has been described in recent epidemiological studies. This association did not appear to be modified by sex, age, country, or time since CA test, whereas the role played by exposure to carcinogens is still uncertain because of the requisite information concerning occupation and lifestyle was lacking. We evaluated in the present study whether CAs predicted cancer because they were the result of past exposure to carcinogens or because they were an intermediate end point in the pathway leading to disease. A nested case-control study was performed on 93 incident cancer cases and 62 deceased cancer cases coming from two prospective cohort studies performed in Nordic countries (Denmark, Finland, Norway, and Sweden) and Italy. For each case, four controls matched by country, sex, year of birth, and year of CA test were randomly selected. Occupational exposure and smoking habit were assessed by a collaborative group of occupational hygienists. Logistic regression models indicated a statistically significant increase in risk for subjects with a high level of CAs compared to those with a low level in the Nordic cohort (odds ratio, 2.35; 95% confidence interval, 1.31-4.23) and in the Italian cohort (odds ratio, 2.66; 95% confidence interval, 1.26-5.62). These estimates were not affected by the inclusion of occupational exposure level and smoking habit in the regression model. The risk for high versus low levels of CAs was similar in subjects heavily exposed to carcinogens and in those who had never, to their knowledge, been exposed to any major carcinogenic agent during their lifetime, supporting the idea that chromosome damage itself is involved in the pathway to cancer. The results have important ramifications for the understanding of the role played by sporadic chromosome damage for the origin of neoplasia-associated CAs.
Adult↗
Miscarriages and stillbirths in women with a high intake of fish contaminated with persistent organochlorine compounds.
OBJECTIVES: The purpose of the present study was to assess the effect, on miscarriages and stillbirths, of persistent organochlorine compounds (POC) through dietary intake of fatty fish from the Baltic Sea. METHODS: Information on miscarriages and stillbirths was collected retrospectively by a self-administered questionnaire in a cohort of fishermen's wives from the Swedish east coast (by the Baltic Sea) and in a referent cohort of west coast fishermen's wives. Current fish consumption was used as a proxy for exposure within the east coast cohort. RESULTS: No increase in miscarriages or stillbirths was found in the east coast cohort compared with the west coast group, in fact a decrease in early miscarriages was found (OR 0.48 [95% CI 0.26-0.92]). Moreover, no increase in risk was found for current high consumers of fatty fish within the east coast cohort. CONCLUSIONS: The present data provided no evidence that dietary POC exposure increases miscarriage and stillbirth rates.
Abortion, Spontaneous↗
IPCS guidelines for the monitoring of genotoxic effects of carcinogens in humans. International Programme on Chemical Safety.
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.
Carcinogens↗
Survival time in a population-based consecutive series of adult acute myeloid leukemia--the prognostic impact of karyotype during the time period 1976-1993.
A consecutive population-based series of 372 adult acute myeloid leukemias, successfully cytogenetically investigated at a single center between 1976 and 1993, is reported. All medical records were reviewed in order to ascertain the prognostic impact of karyotype, divided into three groups; favorable (t(8;21), t(15;17), and inv(16) irrespective of karyotypic complexity; n = 40), poor (der(1;7), inv(3), -5, del(5q), -7, t(9;22), and complex karyotypes including whole or partial losses of chromosomes 5 and/or 7; n = 56), and intermediate (other abnormalities or normal karyotype; n = 276). The possible modification by age, gender, time period, morphologic subtype, and bone marrow transplantation (BMT) on this prognostic impact was also determined. The chemotherapy regimens used were heterogeneous over time but principally the same at any given point in time. The majority of the patients were treated with combinations including an anthracycline and cytarabine with curative intent. Gender, morphology, and BMT did not significantly modify the effect of cytogenetic patterns on survival time, whereas age and time period did. The hazard ratios for the subgroups favorable, intermediate, and poor were 1.0, 1.2 and 1.9 at age 20-49; 1.0, 2.5 and 4.5 at age 50-64; 1.0, 4.1 and 11.4 at age 65-74; 1.0, 1.4 and 2.2 for the time period 1976-1987 and 1.0, 2.0 and 6.7 for 1988-1993. The salient feature of the Kaplan-Meier curves was the improved survival during the later time period for patients with favorable and intermediate cytogenetic abnormalities. The present findings thus suggest that it is mainly these patient groups that have benefited from advances in therapy, including supportive care.
Acute Disease↗
CYP1A1 and GSTM1 polymorphisms affect urinary 1-hydroxypyrene levels after PAH exposure.
Certain human biotransformation enzymes have been implicated in the formation and scavenging of the ultimate reactive metabolites, the diolepoxides, from polycyclic aromatic hydrocarbons (PAHs). In the present study, performed on aluminum smelter workers, we have analyzed airborne PAH, the pyrene metabolite 1-hydroxypyrene (1-OHP) in urine, and genotypes for biotransformation enzymes involved in PAH metabolism. The aim was to evaluate the correlation between external exposure and biomarkers of exposure and to investigate to what extent genetic polymorphism in metabolic enzymes can explain interindividual variation in urinary 1-OHP levels. DNA was prepared from blood samples from 98 potroom workers and 55 controls and altogether eight polymorphisms in the CYP1A1, mEH, GSTM1, GSTP1 and GSTT1 genes were analyzed. The 1-OHP excretion was found to correlate significantly (P </= 0.005) to the exposure. The interindividual difference in excretion of 1-OHP was vast (>100-fold) and univariate and multivariate regression analyses were used to find the variables that could determine differences in excretion. The variation could, to some degree, be explained by differences in exposure to airborne particulate-associated PAHs, the use of personal respiratory protection devices, smoking habits and genetic polymorphisms in the cytochrome P450 1A1, GSTM1 and GSTT1 enzymes. The part of the variance that could be explained by differences in biotransformation genotypes seemed to be of the same order of magnitude as the variance explained by differences in exposure. In the control group as well as in the occupationally exposed group, the highest 1-OHP levels were observed in individuals carrying the CYP1A1 Ile/Val genotype who were also of the GSTM1 null genotype. The results show that urinary 1-OHP is a sensitive indicator of recent human exposure to PAHs and that it may also to some extent reflect the interindividual variation in susceptibility to PAHs.
Aluminum↗
Smoking and myelodysplastic syndromes.
The purpose of this case-control study was to investigate tobacco smoking as a risk factor for myelodysplastic syndromes, emphasizing karyotypic aberrations as markers for exposure and risk differentiation with respect to morphology. We obtained smoking history by interview of 330 cytogenetically investigated adult myelodysplastic syndrome cases and 337 controls, matched with respect to sex, year of birth, and county of living. Smoking for at least 1 year at some time 20 years or less before diagnosis was associated with an elevated relative risk (RR) for primary myelodysplastic syndromes (odds ratio (OR) 1.8; 95% confidence interval (CI) = 1.2-2.7). The results indicated a relation with intensity and duration of smoking as well as a decrease in risk a few years after cessation of smoking. Smoking was associated with an increased RR for primary myelodysplastic syndromes with chromosome 7 abnormalities (OR 5.0; 95% CI = 1.1-23). Elevated RRs were also seen for refractory anemia (OR 2.5; 95% CI = 1.2-5.6) and for refractory anemia with ringed sideroblasts (OR 3.2; 95% CI = 0.88-12). The findings suggest that smoking is a risk factor for myelodysplastic syndromes.
Aged↗
Hypopituitary females have a high incidence of cardiovascular morbidity and an increased prevalence of cardiovascular risk factors.
We recently reported that female patients with hypopituitarism receiving controlled thyroid and steroid hormone substitution, but without GH replacement, had a more than 2-fold increase in cardiovascular mortality compared to the general population. In the present study we investigated the incidence of cardiovascular disease as well as the prevalence of cardiovascular risk factors in 33 females with hypopituitarism for 6-46 yr (median, 18) compared to those in 33 control subjects recruited from the general population in the same geographical area and matched for sex, age, smoking habits, educational level, and residence location. The patients were with a very high probability GH deficient, as 29 had subnormal serum insulin-like growth factor I levels, and the other 4 were GH deficient, as assessed by an insulin tolerance test. The incidence of cardiovascular disease was significantly higher among the hypopituitary patients (incidence ratio, 3.7; 95% confidence interval, 1.2-11.3), and the consumption of cardioactive drugs was also significantly higher (P = 0.002). Hypopituitary patients had a lower degree of physical exercise during their spare time (P = 0.02), a higher waist/hip ratio (P = 0.01), lower high density lipoprotein cholesterol (P = 0.002), and higher low density/high density lipoprotein ratio (P = 0.009). Furthermore, the patients had a significantly increased left atrium size (P = 0.05), but no difference was observed for other cardiac measures. In the patients, serum insulin-like growth factor I levels significantly correlated with left ventricular mass index (r = 0.48; P = 0.006), suggesting that GH has a strong impact on cardiac size. More episodes of bradycardia (P = 0.05), but no increased occurrence of extrasystolies, were encountered in the patients during 24-h continuous electrocardiogram monitoring. Carotid artery intima-media thickness and plaque numbers did not differ between patients and controls. In conclusion, hypopituitary females exhibit an increased incidence of cardiovascular disease, higher cardioactive drug consumption, and an increased prevalence of cardiovascular risk factors. The increased cardiovascular morbidity could not be ascribed to inadequate estrogen or thyroid hormone treatment, and unsubstituted GH deficiency is probably an important contributing factor.
Adult↗