A novel preparative regimen for autologous transplant in non-Hodgkin's lymphoma: long-term experience with etoposide and thiotepa.

The purpose of this study was to evaluate the efficacy and toxicity of the preparative regimen of thiotepa and etoposide in patients undergoing autologous transplantation for relapsed non-Hodgkin's lymphoma. The study involved 65 consecutive patients who underwent autologous transplantation using the thiotepa/etoposide regimen for relapsed intermediate-grade NHL at the University of Wisconsin Hospital and Clinics (UWHC) between 1987 and 2001. The regimen consisted of thiotepa 300 mg/m(2)/day and etoposide 700 mg/m(2)/day on days -6, -5, and -4. The median age at the time of transplant was 49 years. A total of 50 patients (76%) had diffuse large-cell lymphoma. A total of 50 (77%) patients had chemosensitive disease, and 15 (23%) were chemoresistant. With a median follow-up of 34 months (range, 3-163), 28 patients (43%) remain in CR and 33 (51%) have developed recurrent or progressive disease. The overall survival and event-free survival at 3 years are 40% (95% CI 26-53%) and 32% (95% CI 20-45%), respectively. There was one death attributed to regimen-related toxicity (RRT). Reversible gastrointestinal toxicity was the major RRT, and there was minimal pulmonary and cardiac toxicity. We conclude that the combination of thiotepa and etoposide is an effective preparative regimen with acceptable RRT.

Molecular markers of exposure to cadmium and nickel among alkaline battery workers.

T he goal of the study wasto evaluate the usefulness of metallothionein mRNA, anti-5- hydroxymethyl-2'-deoxyuridine antibodies titres (anti-HMdU Ab), and 8-hydroxydeoxyguanosine (8OHdG) in urine as markers of the biologically active dose after exposure to airborne cadmium and nickel in human studies. Exposed persons (n = 38) were chosen from workers involved in the production and assembly, chemistry, and maintenance departments of a nickel-cadmium battery factory in Poland. Controls (n = 52) were chosen from administration personnel at the factory. Biological samples from workers were collected twice: once in the summer, after a month of vacation, and again in the winter, after 3 months of regular working activity within the plant. Controls were recruited during the second phase of the study. When exposure groups were defined on the basis of ambient air cadmium measurements, we found a two-fold increase in mean metallothionein mRNA values in the highest exposure group (air cadmium above 1000 g m-3) and a positive correlation of metallothionein mRNA with blood cadmium levels (r = 0 46, p < 0 008). Future studies can be designed to investigate further the interand intra-subject component of the variability and the possibility of the existence of M T gene polymorphisms, determining different responses and susceptibilities to cadmium exposure. We did not find any difference in the mean values of anti-HMdU Ab titres and 8OHdG in urine in any of the exposure groups analysed. Nickel exposure appeared to have greater impact on anti-HMdU Ab titres than cadmium.

[Frequency of birth defects in newborns in four regions of Poland]. / Czestosc wad wrodzonych u noworodków w czterech regionach Polski.

Records of births from registry offices in seven provinces (Walbrzych, Piotrków Trybunalski, Suwalki, Krosno, Rzeszów, Przemysl, Tarnobrzeg) making four regions (south-western, central, north-eastern and south-eastern) were used for the analysis of the geographical distribution of congenital malformations. This area is inhabited by approximately 10% of the whole population with annual number of briths equal to 9% of the total number in Poland. The incidence of congenital malformations was analysed in 21.167 newborns taking into consideration such variables as smoking and other habits and occupational of parents, maternal age, and environmental pollution. In the cohort under study the incidence of malformations was different and it was as follows: Walbrzych-1.92%, Rzeszów-1.42%, Tarnobrzeg-1.37%, Suwalki-1.23%, Krosno-1.16%, Piotrków Trybunalski-1.12% and Przemysl-0.7%. The incidence of birth defects in infants born to young mothers (< 20 years) was 1.8% and to older ones (> 35) 1.9%. A comprehensive analysis of the environmental pollution revealed its highest level in the south-western region (the Walbrzych province) in comparison with other study areas.

Human metallothionein gene expression determined by quantitative reverse transcription-polymerase chain reaction as a biomarker of cadmium exposure.

Expression of the metallothionein (MT) gene in frozen human lymphocytes has been developed as a new molecular biomarker of heavy metal exposure. Workers at a Polish battery factory with high exposure to cadmium were monitored for airborne exposure and blood cadmium levels. A novel quantitative reverse transcription-PCR (RT-PCR) technique, making use of a homologous internal standard, was used to assess the level of MT-specific mRNA in frozen stored aliquots of blood samples taken from exposed and control workers. Results from this assay showed a statistically significant 2.5-fold increase in MT mRNA in exposed compared to control workers. The RT-PCR results also showed significant correlation with airborne cadmium, as registered on personal monitors and with blood cadmium levels. The results suggest that gene induction measured by quantitative RT-PCR is a promising approach for application as a biomarker of biologically effective dose in small samples of frozen tissues or cells.

Effect of oral Sulfenamide TS administration on prenatal development in rats.

Sulfenamide TS (N-cyclohexyl-2-benzothiazolesulfenamide), accelerator of rubber vulcanization, was administered to female rats by gavage at doses of 50, 150, and 450 mg/kg (1%, 3%, and 8% of LD50) during organogenesis. The maternal toxicity of Sulfenamide TS was found at the highest dose of 450 mg/kg. Oral administration of this compound to female rats during organogenesis induced fetotoxic effects at doses of 50 mg/kg and higher. The dose-dependent increase in the frequency of fetuses/ litters with internal hydrocephalus was observed.

Evaluation of oral exposure to Polnoks R for female rats in developmental toxicity studies.

This study was performed to evaluate the effects of prenatal development of rats exposed to Polnoks R, an antioxidant in elastomer processing. Pregnant female rats were exposed to Polnoks R by gavage every day on days 6-15 of gestation at doses of 170, 340, and 670 mg/kg body weight (b,w) (6%, 13%, and 25% LD50). Clinical observations, maternal body weights, and food and water consumption were recorded throughout gestation. At scheduled necropsy on 20 day of gestation maternal animals were evaluated for body weight, liver, spleen, ovarjan kidney, and adrenal weights, number of ovarian corpora lutea, and status of uterine implantation sites. Fetuses were counted, weighed, and examined for external, skeletal, and visceral alterations. Maternal weight gain was reduced in the group receiving Polnoks R at the 670 mg/ kg dose. In all groups the daily food and water consumptions were similar to controls. The relative weights of the adrenals, ovaries, spleen, and liver of the females intoxicated with the highest dose of Polnoks R were significantly higher than control organs. Polnoks R is an embryotoxic and fetotoxic agent. It produced a significant increase in the average number of postimplantation losses and a decrease in both the weight and body length of the fetuses from the pregnant female rats exposed to the highest dose. This chemical also produced birth defects-absent or short tail, cleft palate, and internal hydrocephalus-but only at doses toxic to the mother.

[Mortality of workers in the dye industry. I. Analysis of general mortality]. / Umieralnosc pracowników przemyslu barwnikarskiego. I. Analiza umieralnosci ogólnej.

A mortality study was carried out among workers employed in a plant producing different kinds of dyes using benzidine. The cohort comprised 8,523 males and 2,006 females whose vital status was recorded between Jan 1, 1945 and Dec 31, 1991. They had worked in this plant for, at least, 3 months between Jan 1, 1945 and Dec 31, 1974. The cohort was divided into 4 subcohorts: I. those exposed only to benzidine; II. those exposed to benzidine and to other occupational hazards; III. those involved directly in the dyes production but not exposed to benzidine, and IV. those not involved directly in the dye production-mainly administrative staff. Death risk was estimated on the basis of standardized mortality ratio (SMR), determined by means of the person-years method. The general population of Poland was taken as a reference group. The observed number of deaths in the cohort and each subcohort was compared with expected deaths. The comparison was based on the national rates by adjustment for age, gender and calendar time. An excessive mortality due to mental disorders (SMR = 2.37) was found in the male cohort, and due to atherosclerosis in both cohorts--male (SMR = 1.25) and female (SMR = 1.37). An analysis of mortality in subcohorts showed similar but not the same relationship. Mortality because of malignant neoplasms will be presented in the next paper.

[Mortality among the dye industry workers. II. An analysis of malignant neoplasm mortality]. / Umieralnosc pracowników przemyslu barwnikarskiego. II. Analiza umieralnosci z powodu nowotworów zlosliwych.

A mortality study was carried out among workers employed in a plant producing different kinds of dyes, including benzidine. The cohort comprised 8,523 males and 2,006 females whose vital status was recorded between Jan 1, 1945 and Dec. 31, 1991. They had worked in this plant for, at least, 3 months between Jan. 1, 1945 and Dec 31, 1974. The cohort was divided into 4 subcohorts: I. those exposed only to benzidine: II. those exposed to benzidine and other occupational hazards; III. those involved directly in the dye production but not exposed to benzidine, and IV. those not involved directly in the dye production-mainly administrative staff. Death risk was estimated on the basis of standardized mortality ratio (SMR) determined by means of the person-years method. The general population of Poland was taken as a reference group. The observed number of deaths in the cohort and each subcohort was compared with expected deaths. The comparison was based on national rates by adjustment for age, gender and calendar time. Significant excessive mortality due to cancer of urinary bladder was observed in the male subcohort I (SMR = 14.69), II (SMR = 16.34) and III (SMR = 3.17); due to malignant neoplasm of pancreas in the male subcohort II (SMR = 3.26); due to malignant neoplasm of testis in the male subcohort III (SMR = 3.17); due to malignant neoplasm of pancreas in the male subcohort II (SMR = 3.26); due to malignant neoplasm of testis in the male subcohort III (SMR = 3.23). Significant excessive mortality due to malignant neoplasm of liver and intrahepatic bile ducts was found in the female subcohort IV (SMR = = 2.36).

Occupational exposures to Cd, Ni, and Cr modulate titers of antioxidized DNA base autoantibodies.

This study was undertaken to establish whether occupational exposures to derivatives of carcinogenic metals evoke inflammatory immune responses, as determined by the presence of elevated titers of antibodies (Ab) that recognize oxidized DNA bases. Sera obtained from the blood of steel welders (Delaware) and from workers of the Centra Ni-Cd Battery Factory (Poznan, Poland) were analyzed by the enzyme-linked immunosorbent assay. To determine specific and nonspecific binding, an oxidized thymidine [5-hydroxymethyl-2'-deoxyuridine (HMdU)] coupled to bovine serum albumin (HMdU-BSA) as well as mock-coupled BSA (M-BSA) were used as antigens for coating the wells of microtiter plates. Titers of anti-HMdU Ab were significantly elevated in the high Cd and Ni exposure groups (18.3 +/- 3.2 vs 10.8 +/- 2.1 A492/microliters; p < 0.05). The sera of the groups with low exposures to Cd and Ni also had enhanced titers of those Ab but those increases were not statistically significant. Interestingly, the Ab titers present in the sera of controls for Cd and Ni exposures appear to be constant regardless of the protein content. In contrast, both lightly and heavily exposed subjects exhibited Ab titers that increased with increasing protein content. When 12 randomly selected workers (4 from each of the control, lightly, and heavily exposed groups) were outfitted with personal monitors, anti-HMdU Ab titers of those workers showed a significant difference between the groups with light (< 100 micrograms/m3) and heavy (> 200 micrograms/m3) exposures to Cd (9.8 +/- 3.7 vs 22.1 +/- 3.7 A492/microliters; p < 0.01) and Ni (11.7 +/- 1.4 vs 31.0 +/- 1.8; p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Assessment of the effect of n-butanol given to female rats in drinking water on fertility and prenatal development of their offspring.

Female rats were given aqueous solutions of n-butanol containing 0.24, 0.8 and 4% n-butanol (0.3; 1.0 and 5.0 g/kg/day) for 8 weeks before and during gestation. The control animals received tap water. The experiment was performed in two stages. The first comprised of the assessment of the oestrous cycle before exposure and then during 4-5 and 7-8 weeks of exposure, and the second stage of the fertility of female rats and their foetal development. The duration of the cycle and its individual stages in the control and the exposed females were similar. It was found that n-butanol alcohol is a foetotoxic agent and produces developmental anomalies in a foetus's skeleton and central nervous system.

[Intracellular receptors of polyaromatic hydrocarbons]. / Wewnatrzkomórkowe receptory wielopierscieniowych weglowodorów aromatycznych.

Molecular aspects of the expression of genes responsible for coding the proteins which participate in the oxidative metabolism of polyaromatic hydrocarbons (PAH) have been discussed. Particular attention has been paid to the expression of the gene for the intracellular PAH-binding AHR protein receptor. Possible relationship between genetically-conditioned polymorphism of PAH oxidative metabolism and individual susceptibility to lung cancer has been presented. Methods for assessment of the affinity of AHR protein to PAH which make it possible to assess human susceptibility to carcinogens have been reviewed.

Potential carcinogenicity assessment of alpha-aescin and phenbendasol.

Potential carcinogenic activity of alpha-aescin and phenbendasole made by "Polfa" (Poland) as well as phenbendasole produced by "Hoechst" (Germany) was studied using Salmonella/microsome test, DNA repair test and micronucleus assay. None of tested preparations were mutagenic or genotoxic what suggest that none of them possess potential carcinogenic activity. Besides, it was established that alpha-aescin exhibits strong and phenbendasol weak acute systemic toxicity for mice. Alpha-aescin and phenbendasole produced in Poland have been found to be toxic for bone marrow cells of mice but only when administered at a high dose of 80% LD50.

[Quantitative risk assessment: extrapolation methods from high doses to low doses]. / Ilosciowa ocena ryzyka: metody ekstrapolacji z wysokich dawek do niskich.

Two methods of linear extrapolation from high to low doses were discussed. The first method depended on fitting a particular model (multistage, logistic) from the experimental data and then on extrapolating from the point on the dose-response curve to the lowest positive dose level employed. The linearized multistage model of carcinogenesis was used in the second method--the results obtained were highly conservative.

[N-acetylation polymorphism versus differentiation of organic susceptibility to carcinogenic effect of homo- and heterocyclic aromatic amines]. / Polimorfizm N-acetylacji a zróznicowanie podatnosci narzadowej na kancerogenne dzialanie amin aromatycznych homooraz heterocyklicznych.

Smoking and consumption of fried and smoked meat play, besides occupational exposure, a significant role in the etiology of neoplasm induced by chemical carcinogens. Homo- and heterocyclic aromatic amines which are present in tobacco smoke and generate during meat processing are of special concern. Homocyclic aromatic amines are mainly responsible for inducing neoplasm of bladder while heterocyclic amines induce neoplasm of colon. Acetyltransferase is essential in transformation of cells in both groups of aromatic amines. The studies carried out so far indicate that persons displaying low cellular activity of acetyltransferase, so called slow acetylators, are more susceptible to neoplasm of bladder under condition of exposure than those displaying high acetyltransferase activity (fast acetylators). However, under exposure to heterocyclic aromatic amines fast acetylators are more susceptible to neoplasm of colon than slow acetylators. The distinction between fast and slow acetylators as for as susceptibility to neoplasms of bladder and colon is concerned results from different nature of metabolism homo- and heterocyclic aromatic amines undergo in the liver.

Genotoxicity assessment of Rokanol B2 and Rokamid R1.

Two surface-active compounds, Rokanol B2 and Rokamid R1, were examined with three types of screening tests: 1. standard Ames test in vitro using S. typhimurium TA97a, TA98, TA100 and TA102 strains; 2. micronucleus test in vivo; 3. sister chromatid exchange (SCE) on bone marrow cells of Balb C mice. Negative results of the testing, in terms of the effects of activity of both the technical preparations on S. typhimurium cells and bone marrow of Balb C mice, were found for both tested chemicals.

Effects of the workplace on fertility and related reproductive outcomes.

This report reviews the recent literature on the adverse effects of occupational factors on fertility and related reproductive outcomes. Few studies fulfill the criteria of good study design because of small sample size, insensitive measures of effect, selection, recall, and observation bias, weak if any control of confounding factors, bad definition of exposure, inability to analyze a dose-response relationship, and inadequate statistical analysis. The high prevalence of unsuccessful reproductive outcomes in the general population makes the design of human fertility studies difficult. Although a number of publications indicate that certain occupational factors and settings adversely affect both male and female fertility, it is virtually impossible to estimate the proportion of infertility due to occupational factors in the general population. The collected data suggest that the exposure to the following substances or occupational settings may affect a function of male genital system, leading to sperm abnormalities, hyperestrogenism, impotence, infertility, and/or increased spontaneous abortion rate in wives of exposed workers: alkylmercury, antimonide, anesthetic gases, boron, carbon disulfide, chlorodecone, chloroprene, some carbamates (carbaryl), diaminostilbene, 1,2-dibromo-3-chloropropane, ethylene glycol ethers, ethylene dibromide, inorganic lead, manganese, methyl chloride, organic solvents, synthetic estrogens and progestins, tetraethyllead, combined exposure to styrene and acetone, welding operations, and heat. The majority of reviewed papers on female fertility concerns the alterations of menstrual cycle and pregnancy complications rather than occupational exposure-induced female infertility. The literature supports the hypothesis that, in general, working women have a tendency of higher risk of unsuccessful reproductive outcomes, although the existing data are not sufficient.

[Hormesis and stress responses of human cells to chemical and physical hazards present at work places]. / Hormetyczna i stresowa odpowiedz komórek organizmu ludzkiego na szkodliwosci chemiczne i fizyczne obecne w miejscu pracy.

Such a phenomenon when very low doses of harmful chemical or physical agent make the cell "ready" to remain completely indifferent to higher doses of this agent is called hormesis, and factors which evoke this phenomenon--hormetic factors. The majority of hormetic factors are also stress to cells. This suggests that cell mechanisms evoked by hormetic and stress factors are similar. Among occurrence which accompany the cell hormesis and stress, polypeptides called "stress" and "shock" proteins play an important role. Proteins synthesized in conditions of thermal shock, so called proteins of thermal shock (Hsp) are especially well known. Proteins of Hsp70 and Hsp90 families as well as ubiquitin belong to the same group. Proteins of thermal shock are indispensable for protecting cells against a destructive effect of exogenous chemical and physical agents. Understanding of mechanisms associated with cell hormesis and stress is of great importance for occupational medicine. It has been found out that exposure, especially to low doses of harmful factor, does not always produce adverse health effects in an exposed organism.

[Quantitative risk assessment of environmental health hazards: exposure,risk and hazard]. / Ilosciowa ocena srodowiskowego ryzyka zdrowotnego: narazenie, ryzyko, zagrozenie.

The setting of regulations which are aimed at reducing or eliminating the effects of exposure should be preceded by the risk assessment procedures. The quantitative risk assessment is one of the methods to estimate the probability of adverse health effects caused by the exposure. In this paper the fundamental notions of exposure, risk and hazard have been discussed. The quantitative risk assessment includes four steps: hazard identification, exposure evaluation and assessment of the relationship between the level of exposure and the occurrence of adverse health effects (dose-response relationship) and risk characterization. It should be stressed that the numerical values obtained from the risk assessment should be considered in combination with other relevant data available, rather than be regarded as direct indices. Then the risk assessment will allow estimating the most likely range of risk for a particular hazard under study.