Search PubMed⌕ Search

Biomedical subjects

M T Landi

Publications and source records attributed to M T Landi.

At least 19 recordsLinked to original sources
PubMed2005

Health status and plasma dioxin levels in chloracne cases 20 years after the Seveso, Italy accident.

BACKGROUND: The Seveso, Italy accident of 1976 exposed a large population to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or simply dioxin). The accident resulted, mostly among children, in one of the largest ever-reported outbreaks of chloracne, the typical skin disorder due to halogenated-hydrocarbon compounds. OBJECTIVES: Approximately 20 years after the accident, we conducted an epidemiological study in Seveso to investigate (a) the health status of chloracne cases; (b) TCDD-chloracne exposure-response relationship; and (c) factors modifying TCDD toxicity. METHODS: From 1993 to 1998, we recruited 101 chloracne cases and 211 controls. Trained interviewers administered a structured questionnaire assessing, among other epidemiological variables, information on an extensive list of diseases. During the interview, individual pigmentary characteristics were determined. We measured plasma TCDD levels using high-resolution gas chromatography/mass spectrometry. RESULTS: Plasma TCDD was still elevated (> 10 ppt) in 78 (26.6%) of the 293 subjects with adequate plasma samples, particularly in females, in subjects who had eaten home-grown animals, and in individuals with older age, higher body mass index and residence near the accident site. After 20 years, health conditions of chloracne cases were similar to those of controls from the Seveso area. Elevated plasma TCDD was associated with chloracne [odds ratio (OR) = 3.7, 95% confidence interval (CI) 1.6-8.8, adjusted for age, sex and residence]. Chloracne risk was higher in subjects younger than 8 years at the accident (OR = 7.4, 95% CI 1.8-30.3) and, contrary to previous hypotheses, did not increase at puberty onset or in teenage years. Subjects with elevated TCDD levels and light hair colour had higher relative odds of chloracne (OR = 9.2, 95% CI 2.6-32.5). CONCLUSIONS: Dioxin toxicity in chloracne cases was confined to the acute dermatotoxic effects. Chloracne occurrence appeared related to younger age and light hair colour. Age-related dioxin elimination or dilution must be taken into account in interpreting these results.

Accidents, Occupational↗
PubMed2004

XPD gene polymorphism and host characteristics in the association with cutaneous malignant melanoma risk.

We recently reported an association between low DNA repair capacity, measured through the host-cell reactivation assay, and melanoma risk in subjects with dysplastic naevi or low tanning ability. We investigated the genetic basis for these findings by analysing the Asp312Asn and Lys751Gln polymorphisms of the XPD (ERCC2) DNA repair gene in the same subjects. Similar to our previous report, no significant association between XPD polymorphisms and melanoma risk was found in 176 melanoma cases and 177 controls (odds ratio (OR)=1.5, 95% confidence interval (CI)=0.9-2.5 for 312Asn; OR=1.3, 95% CI=0.8-2.1 for 751Gln, adjusted for age, gender, dysplastic naevi and pigmentation characteristics). However, XPD variants were associated with increased risk in older (>50 years) subjects (OR=3.4, 95% CI=1.6-7.3 for 312Asn; OR=2.3, 95% CI=1.1-4.9 for 751Gln). The 751Gln allele was associated with elevated melanoma risk among subjects without dysplastic naevi (OR=2.6, 95% CI=1.1-6.4). Subjects with low tanning ability and XPD variants exhibited a nonsignificant increase of melanoma risk (OR=2.3, 95% CI=0.7-7.0 for 312Asn; OR=3.0, 95% CI=1.0-8.8 for 751Gln). DNA repair capacity was slightly decreased in subjects carrying 751Gln alleles. XPD variants may modify melanoma risk in subjects with specific host characteristics, such as older age, lack of dysplastic naevi or low tanning ability.

Adolescent↗
PubMed2001

Combined risk factors for melanoma in a Mediterranean population.

A case-control study of non-familial melanoma including 183 incident cases and 179 controls was conducted in North-Eastern Italy to identify important risk factors and determine how combination of these affects risk in a Mediterranean population. Presence of dysplastic nevi (OR = 4.2, 95% CI = 2.4-7.4), low propensity to tan (OR = 2.4, 95% CI = 1.1-5.0), light eye (OR = 2.4, 95% CI = 1.1-5.2), and light skin colour (OR = 4.1, 95% CI = 1.4-12.1) were significantly associated with melanoma risk after adjustment for age, gender and pigmentation characteristics. A chart which identifies melanoma risk associated with combinations of these factors is presented; it can be used to identify subjects who would most benefit from preventive measures in Mediterranean populations. According to the combination of these factors, a relative risk range from 1 to 98.5 was found. Light skin colour, high number of sunburns with blistering, and low propensity to tan were significantly associated with melanoma thickness, possibly indicating that individuals with these characteristics underestimate their risk and seek attention when their lesion is already advanced.

Adolescent↗
PubMed1999

Human cytochrome P4501A2.

CYP1A2, a member of the cytochrome P450 superfamily (CYPs), is involved in the metabolic activation of several carcinogens, among them aromatic and heterocyclic amines, nitroaromatic compounds, mycotoxins and estrogens. Several drugs are also metabolized by CYP1A2. Individual differences in CYP1A2 activity may thus influence individual susceptibility to cancer risk and the therapeutic efficacy of some drugs. In humans, CYP1A2 has been detected only in the liver, where it seems to be regulated by at least two mechanisms, one controlling constitutive levels of expression and another regulating inducibility. Wide interindividual differences in CYP1A2 activity have been described. They may be due to factors such as gender, race, genetic polymorphisms, and exposure to inducers. Higher activity has been shown in men than in women. Wide variation across racial/ethnic groups has been reported. Overall, slow and intermediate CYP1A2 metabolizers represent about 50% of Caucasians, while their frequency in Japanese subjects seems to be much lower. No nucleotide differences that could explain the phenotypic variability of the CYP1A2 gene have been found in any exons, exon-intron junctions, or 5'-flanking regions of the gene. However, two genetic variants have been identified which seem to be associated with CYP1A2 inducibility only. Induction of CYP1A2 activity has been reported as a consequence of cigarette smoking, dietary factors, several drugs, chronic hepatitis, and exposure to polybrominated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin. Several epidemiological studies have been conducted into the relationship between CYP1A2 activity, alone or in combination with other CYPs, and cancer risk. In the absence of a genotypic assay, only the CYP1A2 phenotype can be assessed at present. Many compounds have been tested as in vitro probes to assess CYP1A2 activity in humans. Currently, caffeine has the best potential for use in epidemiological studies: metabolites of caffeine after coffee consumption are measured as an index of CYP1A2 activity. Variable results have been obtained with caffeine-based methods, the use of some caffeine metabolite ratios having given bimodal or trimodal distributions while others have suggested normal or unimodal distributions. Although the epidemiological studies are limited because only phenotyping data are available, there is a suggestion of increased risk of colon cancer and bladder cancer in subjects with rapid CYP1A2 activity. A higher level of 4-aminobiphenyl-haemoglobin adducts has also been found in moderate smokers with rapid CYP1A2 phenotype than in subjects with slow activity.

Biotransformation↗
PubMed1998

2,3,7,8-Tetrachlorodibenzo-p-dioxin plasma levels in Seveso 20 years after the accident.

In 1976, near Seveso, Italy, an industrial accident caused the release of large quantities of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) into the atmosphere, resulting in the highest levels of the toxicant ever recorded in humans. The contaminated area was divided into three zones (A, B, R) corresponding to decreasing TCDD levels in soil, and cohort including all residents was enumerated. The population of the surrounding noncontaminated area (non-ABR) was chosen as referent population. Two decades after the accident. plasma TCDD levels were measured in 62 subjects randomly sampled from the highest exposed zones (A and B) and 59 subjects from non-ABR, frequency matched for age, gender, and cigarette smoking status. Subjects living in the exposed areas have persistently elevated plasma TCDD levels (range = 1.2-89.9 ppt; geometric mean = 53.2 and 11.0 ppt for Zone A and Zone B, respectively). Levels significantly decrease by distance from the accident site (p = 0.0001), down to general population values (4.9 ppt) in non-ABR, thus validating the original zone classification based on environmental measurements. Women have higher TCDD levels than men in the entire study area (p = 0.0003 in Zone B; p = 0.007 in non-ABR). This gender difference persists after adjustment for location within the zone, consumption of meat derived from locally raised animals, age, body mass index, and smoking. There is no evidence for a gender difference in exposure, so variation in metabolism or elimination due to body fat or hormone-related factors may explain this finding. Elevated TCDD levels in women may contribute to adverse reproductive, developmental, and cancer outcomes.

Accidents, Occupational↗
PubMed1997

Dioxin exposure and cancer risk: a 15-year mortality study after the "Seveso accident".

Dioxin (2,3,7,8-tetrachlorodibenzo-para-dioxin, or TCDD) is a powerful carcinogen in experimental animals, whereas the evidence in humans is limited. We examined cancer mortality from 1976 to 1991 among residents of Seveso, Italy, which was highly contaminated after an industrial accident. The area was divided into zones with decreasing exposure to dioxin (A = highest, B = lower, R = lowest). The population of a surrounding noncontaminated area was used as a reference group. Zone A was small (11,516 person-years); in that zone, we saw a moderate increase in mortality from digestive cancer among women [relative risk (RR) = 1.5; 95% confidence interval (CI) = 0.5-3.5]. In zone B, we also saw excesses at digestive sites (83,610 person-years), 10 years after the accident. Women had an increased mortality from stomach cancer (RR = 2.4; 95% CI = 0.8-5.7), and men had increased mortality from rectal cancer (RR = 6.2; 95% CI = 1.7-15.9). Hematologic neoplasms were increased. The highest risks were seen in zone B for leukemia in men (RR = 3.1; 95% CI = 1.3-6.4), multiple myeloma in women (RR = 6.6; 95% CI = 1.8-16.8), and Hodgkin's disease in both genders (RR = 3.3; 95% CI = 0.4-11.9 in men; and RR = 6.5; 95% CI = 0.7-23.5 in women). Soft tissue sarcoma was elevated only among zone R males (256,408 person-years; RR = 2.1; 95% CI = 0.6-5.4). We found no increase for all-cancer mortality or major specific sites (for example, respiratory among males, breast among females). The specific excesses that we observed were not explained by bias or confounding, and their association with dioxin exposure is plausible. The follow-up is continuing.

Accidents↗
PubMed1997

Sample collection, processing and storage.

We review issues related to the inclusion of biospecimens in epidemiological studies. Technical advances and the revolution in molecular biology have rendered the use of biomarkers increasingly feasible in epidemiological investigations, however the cost and complexity require interdisciplinary expertise and careful attention to methodological detail in order to ensure validity. The widespread banking of biospecimens for long-term (cohort) studies requires special attention to be paid to these issues. Blood, urine and tumour tissue are in common use in medicine and at least some aspects of sample handling derives directly from this clinical experience, although special considerations apply in the epidemiological setting. An increasingly broad array of biospecimen types have been studied, including exhaled air, nail clippings, buccal cells, saliva, semen, faeces and breast milk. Relevant issues in the processing, storage, shipping, timing of collection and safety procedures are examined in terms of their potential to distort results. The role of carefully developed quality control protocols is emphasized. In order to take full advantage of the opportunities afforded by the use of biomarkers in epidemiological studies, careful attention to biospecimen processing, the stability of the biomarker and the precautions to be taken during transportation and storage of samples is necessary.

Biomarkers, Tumor↗
PubMed1996

Cytochrome P4501A2: enzyme induction and genetic control in determining 4-aminobiphenyl-hemoglobin adduct levels.

Cytochrome P4501A2 (CYP1A2) activity may be related to bladder cancer risk through metabolic activation of aromatic amines, such as 4-aminobiphenyl (ABP), to reactive intermediates that can form DNA and hemoglobin (Hb) adducts. In the context of a study on smoking and bladder cancer risk, 97 healthy male volunteers were investigated. CYP1A2-dependent N-oxidation activity was measured using a molar ratio of urinary caffeine metabolites [(paraxanthine + 1,7-dimethyluric acid)/caffeine] obtained between the fourth and fifth h after drinking a standardized cup of coffee. N-Oxidation activity was induced by blond tobacco smoke, meat consumption the dinner before the test, or more than four cups of coffee a day. The regular use of medication appeared associated with a decrease in N-oxidation levels. Age and alcohol consumption were not related with CYP1A2 activity. A polymorphic distribution of the CYP1A2 and N-acetyltransferase-2 (determined by the caffeine metabolite ratio 5-acetylamino-6-formylamino-3-methyluracil:1-methylxanthine) phenotypes was examined in relation to susceptibility to ABP-Hb adduct formation. Rapid oxidizers and subjects with the combined slow acetylator-rapid oxidizer phenotype showed the highest ABP-Hb adduct levels at a low smoking dose. Blond tobacco smokers exhibited higher adduct levels compared with black tobacco smokers, after adjustment for the quantity of cigarettes smoked. At the highest levels of smoking exposure, no major difference in ABP-Hb adduct levels was found among the different combinations of CYP1A2 and N-acetyltransferase-2 phenotypes. In a subset of only 45 available samples, no association was seen between the ABP-Hb adduct levels and the glutathione S-transferase M1 genotype.

Age Factors↗
PubMed1995

A novel point mutation in a 3' splice site of the NADH-cytochrome b5 reductase gene results in immunologically undetectable enzyme and impaired NADH-dependent ascorbate regeneration in cultured fibroblasts of a patient with type II hereditary methemoglobinemia.

Hereditary methemoglobinemia with generalized deficiency of NADH-cytochrome b5 reductase (b5R) (type II) is a rare disease characterized by severe developmental abnormalities, which often lead to premature death. Although the molecular relationship between the symptoms of this condition and the enzyme deficit are not understood, it is thought that an important cause is the loss of the lipid metabolizing activities of the endoplasmic reticulum-located reductase. However, the functions of the form located on outer mitochondrial membranes have not been considered previously. In this study, we have analyzed the gene of an Italian patient and identified a novel G-->T transversion at the splice-acceptor site of the 9th exon, which results in the complete absence of immunologically detectable b5R in blood cells and skin fibroblasts. In cultured fibroblasts of the patient, NADH-dependent cytochrome c reductase, ferricyanide reductase, and semidehydroascorbate reductase activities were severely reduced. The latter activity is known to be due to b5R located on outer mitochondrial membranes. Thus, our results demonstrate that the reductase in its two membrane locations, endoplasmic reticulum and outer mitochondrial membranes, is the product of the same gene and suggest that a defect in ascorbate regeneration may contribute to the phenotype of hereditary methemoglobinemia of the generalized type.

Amino Acid Sequence↗
PubMed1994

Genetically based N-acetyltransferase metabolic polymorphism and low-level environmental exposure to carcinogens.

The metabolic activation or inactivation of carcinogens varies considerably in human populations, and is partly genetically determined. Inter-individual variability in the susceptibility to carcinogens may be particularly important at low degrees of environmental exposure. Examples of probable human carcinogens that present widespread low-dose exposures are environmental tobacco smoke and diesel exhaust. We have determined levels of DNA adducts in bladder cells and of 4-aminobiphenyl-haemoglobin adducts in 97 volunteers, together with the N-acetylation non-inducible phenotype, the corresponding genotype, and the levels of nicotine-cotinine in the urine. We find that among the slow acetylators, 4-aminobiphenyl adducts were higher than in rapid acetylators at low or null nicotine-cotinine levels, whereas the difference between slow and rapid acetylators was less evident at increasing nicotine-cotinine levels. The N-acetyltransferase genotype is highly predictive of the acetylation phenotype. Our results indicate that the clearance of low-dose carcinogens is decreased in the genetically based slow-acetylator phenotype. Such genetic modulation of low-dose environmental risks is relevant to 'risk assessment' procedures.

Acetylation↗