Abstract  In a comparative study on 135 compounds of various chemical classes, 30 agents inducing direct nonreparable DNA damage in repair-deficient E. coli failed in reverting strains TA1535, TA1537, TA1538, TA98 and TA100 of S. typhimurium (De Flora et al., 1984b). These compounds were re-assayed in the Ames test using strains TA97 and TA102. A dose-dependent mutagenic response was detected with aminoantipyrine and p-rosaniline in TA97 and with streptomycin and formaldehyde in TA102. p-Rosaniline was the only mutagen requiring metabolic activation. 5 compounds, i.e. o-aminophenol in TA97 and methanol, ethanol, cadmium chloride and cadmium sulfate in TA102, induced a reproducible increase in revertants over controls, but this was less than 2-fold. The remaining 21 chemicals--including amino compounds, aliphatics, aromatics, heterocycles, hydrazine derivatives and inorganics--confirmed their inactivity in the Ames test. Overall data for 135 compounds, comparing the Ames test (7 strains) and the DNA-repair test (3 strains), are re-assessed on the basis of these findings.

Abstract  The cytogenetic effect of formaldehyde (FA) on unstimulated human lymphocytes was studied by means of conventional chromosome analysis and the premature chromosome condensation (PCC) technique. In first post-treatment metaphases no significantly increased yields of chromosomal changes could be observed. The analysis of PCCs, however, showed high yields of chromosome fragments. Bleomycin (BLM) used as positive control was also highly clastogenic in PCCs and resulted in significantly increased yields of chromosome-type aberrations. As recently argued, a premitotic selection against heavily damaged cells could be an explanation for the discrepancy between the chromosome findings in metaphase and PCC analysis after FA treatment. In addition, a differential effectiveness may exist in unstimulated lymphocytes to convert multiple fragmentation into chromatid- or chromosome-type aberrations through S-phase-dependent or S-phase-independent mechanisms.

Abstract  Baby nursery cribs, changing tables, and dressers can emit formaldehyde at levels linked with increased risk of childhood allergies and asthma, according to a new report released today by Environment California Research & PolicyCenter. In Toxic Baby Furniture: The Latest Case for Making Products Safe from the Start, Environment California Research & Policy Center worked with an independent laboratory to determine whether formaldehyde emissions from common baby nursery furnishings significantly contribute to indoor air pollution.

Abstract  The derivatization method of thiazolidine-4-carboxylic acid (TZCA) and methyl-thiazolidine-4-carboxylic acid (Me-TZCA) in urine with alcohol/chloroformate was achieved. TZCA and Me-TZCA were derivatized in one step in urine with ethyl chloroformate in 1 min at room temperature. The derivatives of TZCA and Me-TZCA had very good chromatographic properties and offered very sensitive response for gas chromatography-electron impact ionization-mass spectrometry (GC-EI-MS). On the basis of derivatization, the method for simultaneous determination of TZCA and Me-TZCA in human urine was developed. Deuterated Me-TZCA (Me-TZCA-d4) was synthesized as the internal standard (IS) for the analysis of urine samples. TZCA and Me-TZCA were derivatized and extracted from urine at pH 9.5 with toluene, and then the dried extract was dissolved with 100 µl ethyl acetate and injected in GC/MS system. The recoveries of TZCA and Me-TZCA were about 102 and 103%, respectively, at the concentration of 0.05 mg/l. The method detection limits (MDL) were 1.0 and 0.5 µg/l, respectively, for TZCA and Me-TZCA in 1 ml human urine. The coefficients of variation of TZCA and Me-TZCA were less than 6% at the concentrations of 0.05 and 0.2 mg/l, respectively. To assess the formation of TZCA during inhalation with formaldehyde (FA) (about 3.1 and 38.1 ppm FA in air), urine samples from rats were taken during 3 days after initiation of treatment. The mean amount of TZCA determined was 0.07 mg/l in control group and 0.18 mg/l during treatment with 3.1 ppm. The TZCA levels increased up to about 1.01 mg/l during treatment with 38.1 ppm. It is planned to study whether urinary TZCA can be used as an indicator in the biological monitoring of exposure to FA.

Abstract  Biologically-based models of carcinogenesis were originally developed to explain certain quanti-tative phenomena associated with carcinogenesis, and to provide a framework within which questions regarding the process could be addressed. Some limitations in the use of these models for quantitative cancer risk assessment are discussed.

Abstract  Cytogenetic evaluation of 15 employees exposed to formaldehyde in formaldehyde manufacturing and processing for 23 to 35 years (28 years average) revealed no statistically significant increase in chromosome aberration rates as compared with a matched control group.

Abstract  The increasing use of alcohol as an alternative fuel to gasoline or diesel can increase emission of formaldehyde, an organic gas that is irritant to the mucous membranes. The respiratory system is the major target of air pollutants and its major defense mechanism depends on the continuous activity of the cilia and the resulting constant transportation of mucous secretion. The present study was designed to evaluate the effects of formaldehyde on the ciliated epithelium through a relative large dose range around the threshold limit value adopted by the Brazilian legislation, namely 1.6 ppm (1.25 to 5 ppm). For this purpose, the isolated frog palate preparation was used as the target of toxic injury. Four groups of frog palates were exposed to diluted Ringer solution (control, N = 8) and formaldehyde diluted in Ringer solution at three different concentrations (1.25, 2.5 and 5.0 ppm, N = 10 for each group). Mucociliary clearance and ciliary beat frequency decreased significantly in contact with formaldehyde at the concentrations of 2.5 and 5.0 ppm after 60 min of exposure (P<0.05). We conclude that relatively low concentrations of formaldehyde, which is even below the Brazilian threshold limit value, are sufficient to cause short-term mucociliary impairment.

Abstract  In this investigation, the combination of 1-beta-D-arabinofuranosylcytosine and hydroxyurea was used to inhibit the polymerase step of DNA excision repair. The DNA single-strand breaks (SSB), which accumulated in the presence of these agents, were measured by alkaline elution. With this approach, DNA SSB were detected in normal human fibroblasts after exposure to trans-platinum(II)diamminedichloride, formaldehyde, or potassium chromate. These agents all share the common feature that they induce DNA-protein cross-links in mammalian cells. In the case of trans-platinum(II)diamminedichloride or formaldehyde, the frequency of these SSB was markedly less in excision-deficient xeroderma pigmentosum cells. With chromate, a high level of SSB was induced in both normal and xeroderma pigmentosum cells; these results indicate that chromate damage to DNA is repaired by a mechanism different than the classical excision pathway since xeroderma pigmentosum cells responded normally. Several other agents were investigated with this approach, and no SSB were detected with nickel sulfate, 12-O-tetradecanoylphorbol-13-acetate or asbestos fibers in the presence of the polymerase inhibitor. This approach was found to be a very sensitive method to detect DNA excision repair.

Abstract  The upper respiratory tract mucociliary apparatus represents one of the first defenses against inhaled noxious materials. The frog palate has been widely used as a model to investigate the mode of action of this apparatus and to study its response to irritant gases. Video analysis was used here for the determination of mucus flow rate and flow patterns, ciliary beat frequency, and the nature of ciliary activity in the in vitro frog palate preparation. The results of studies of time-lapse video recordings were used in conjunction with light microscopic and ultrastructural morphologic investigations to determine functional interactions between cilia, the epiphase, and the periciliary fluid. It was concluded that the cilia enter the epiphase during the effector stroke, that waves may be produced on the under surface of this layer, and that the periciliary fluid is less viscous than, and moves in the same direction as, the epiphase. The response of the frog palate mucociliary apparatus to formaldehyde gas was also studied using an in vitro exposure system. There were distinct concentration-related responses to formaldehyde with initial stimulation, and at higher concentrations, subsequent inhibition of mucociliary function. Stimulation of mucus flow rate was due to increased ciliary activity, while inhibition of flow, which preceded ciliastasis, was attributed to direct effect of formaldehyde on the superficial mucus layer. Ciliastasis on the other hand was considered to provide evidence that the formaldehyde had penetrated the mucus layer and induced direct toxic effects on the underlying epithelial cells.

Abstract  C3H/10T 1/2 cells were treated with N-methyl-N'-nitro-N-nitrosoguanidine and then repeatedly exposed to formaldehyde (0.1 to 2.0 micrograms/ml). Exposure of N-methyl-N'-nitro-N-nitrosoguanidine-initiated cultures to formaldehyde concentrations of 0.5 or 1.0 micrograms/ml in a variety of treatment regimens resulted in focus formation in up to 9% of the treated dishes. Transformed foci were observed in 2% or less of the cultures treated with N-methyl-N'-nitro-N-nitrosoguanidine or formaldehyde alone. Formaldehyde thus appears to be only a weak tumor promoter for C3H/10T 1/2 cell transformation.

Abstract  In recent decades the prevalence of asthma has been increasing in Western countries. Altered environment and lifestyle conditions have been implicated but the underlying mechanisms remain unclear. The Indoor Pollutants, Endotoxin, Allergens, Damp and Asthma (IPEADAM) study is a cross-sectional, case control study designed to analyse the home environments of 200 children in Manchester. In this paper the home concentrations and relationships to asthma development have been examined for a variety of indoor agents including environmental tobacco smoke (ETS), nitrogen dioxide (NO2), formaldehyde, volatile organic compounds (VOCs) and damp, which have been reported as potential factors in the development or the exacerbation of asthma. Levels of respirable particles and tobacco specific particles were found to be significantly higher in the homes with smokers present, but there were no differences in the levels of NO2, formaldehyde or VOCs. However, there were no significant differences in the levels of tobacco related pollutants in the homes of children with and without asthma. Similarly there were no statistically significant differences in the levels of NO2, formaldehyde, VOCs, temperature or relative humidity between the homes of children with and without asthma. This study has demonstrated that few differences exist between the home environments of English children, between 4-16 years of age, with asthma and those without the disease. The parameters examined in this study are unlikely to be related to the development of asthma. Avoidance of these pollutants may not be beneficial in preventing the development of asthma in this age group.

Abstract  Asthma is now recognized as an epidemic in the developed world, focusing attention on possible therapies. Although much has been learned over the last two decades about the pathogenesis of asthma, this complex disease resists magic-bullet therapies. In part, this resistance may be caused by the large number of genes that interact with underlying physiology and environmental factors to trigger disease. The chronic inflammation of the asthmatic lung results from an allergic reaction marked by elevated immunoglobulin E, mast cells and eosinophils, and cytokines such as interleukin-5 and interleukin-13. This chronic inflammation causes bouts of acute airway constriction. Eventually, asthmatic lungs show permanent changes: increased mucus cell mass, hypertrophy of the smooth muscle cells, and deposition of collagen just below the lining of the epithelial surface.

Abstract  A case-control study was undertaken in Montreal to investigate the possible associations between occupational exposures and cancers of the following sites: oesophagus, stomach, colo-rectum, liver, pancreas, lung, prostate, bladder, kidney, melanoma and lymphoid tissue. In total, 3,726 cancer patients and 533 population controls were interviewed to obtain detailed lifetime job histories and information on potential confounders. Each job history was translated into a history of occupational exposures. Because of current concerns about formaldehyde carcinogenicity, we carried out a special analysis of the association between exposure to formaldehyde and each type of cancer covered by this study. Separate statistical analyses were carried out for each type of cancer using population controls as well as a control series drawn from among the other cancer sites in the study. Although nearly a quarter of all subjects had undergone occupational exposure to formaldehyde, the levels of exposure were in general quite low. There was no persuasive evidence of an increased risk of any type of cancer among men exposed to these levels of formaldehyde. However, the possibility of a small increase in risk could not be ruled out.

Abstract  Each of the Escherichia coli tester strains in the WP3101P–WP3106P series contains an F' plasmid with a different base substitution mutation within the lacZ gene. Each of the six possible base substitution mutations, therefore, can be assayed with these strains by Lac+ reversion. We used the strains to characterize the mutational profiles of 21 chemical mutagens, including alkylating agents, base analogs and oxidative compounds. We also assayed the mutagens with Salmonella typhimurium tester strains TA7002, TA7004 and TA7005, which detect A·T->T·A, G·C->A·T and G·C->T·A mutations, respectively, and we compared the sensitivity and specificity of the two systems. Escherichia coli strain WP3102P was more sensitive than the S.typhimurium strains to G·C->A·T transitions induced by N4-aminocytidine, 5-azacytidine, cumene hydroperoxide (CHP), t-butyl hydroperoxide (BHP), N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG), methyl methane sulfonate and N-ethyl-N-nitrosourea (ENU), while the reverse was true for G·C->A·T transitions induced by 2-aminopurine and phosmet. Escherichia coli strain WP3104P, which detects G·C->T·A transversions, was superior to the S.typhimurium strains in detecting transversions induced by N4-aminocytidine, 5-azacytidine, 5-diazouracil, CHP, BHP, ENNG, ENU, 4-nitroquinoline 1-oxide (4-NQO) and 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX). Escherichia coli WP3105P was also more sensitive than S.typhimurium to A·T->T·A transversions induced by N-methyl-N- nitrosourea (MNU), CHP and 4-NQO, but it was less sensitive to those induced by ENNG, ENU and 2-aminopurine. The present results indicate that the E.coli Lac+ reversion system with tester strains WP3101P–WP3106P is as sensitive as the S.typhimurium His+ reversion system for the detection of specific mutations induced by a variety of direct mutagens.

Abstract  A study was conducted to evaluate the genotoxic effect of occupational exposure to formaldehyde on pathology and anatomy laboratory workers. The level of exposure to formaldehyde was determined by use of passive air-monitoring badges clipped near the breathing zone of 59 workers for a total sampling time of 15 min or 8 h. To estimate DNA damage, a chemiluminescence microplate assay was performed on 57 workers before and after a 1-day exposure. Assessment of chromosomal damage was carried out by use of the cytokinesis-blocked micronucleus assay (CBMN) in peripheral lymphocytes of 59 exposed subjects in comparison with 37 controls matched for gender, age, and smoking habits. The CBMN assay was combined with fluorescent in situ hybridization with a pan-centromeric DNA probe in 18 exposed subjects and 18 control subjects randomized from the initial populations. Mean concentrations of formaldehyde were 2.0 (range <0.1–20.4 ppm) and 0.1 ppm (range <0.1–0.7 ppm) for the sampling times of 15 min and 8 h, respectively. No increase in DNA damage was detected in lymphocytes after a one-workday exposure. However, the frequency of binucleated micronucleated cells was significantly higher in pathologists/anatomists than in controls (16.9‰ ± 9.3 versus 11.1‰ ± 6.0, P = 0.001). The frequency of centromeric micronuclei was higher in exposed subjects than in controls (17.3‰ ± 11.5 versus 10.3‰ ± 7.1) but the difference was not significant. The frequency of monocentromeric micronuclei was significantly higher in exposed subjects than in controls (11.0‰ ± 6.2 versus 3.1‰ ± 2.4, P < 0.001), while that of the acentromeric micronuclei was similar in exposed subjects and controls (3.7‰ ± 4.2 and 4.1‰ ± 2.7, respectively). The enhanced chromosomal damage (particularly chromosome loss) in peripheral lymphocytes of pathologists/anatomists emphasizes the need to develop safety programs.

Abstract  We have found formaldehyde to be mutagenic for human cells in culture. At concentrations above 130 μM or 4 parts per million by weight (2 h exposure at 37°C), formaldehyde induces the appearance of F3TdR-resistant mutants in the diploid human lymphoblastoid TK6 line. This finding suggests but does not prove that formaldehyde is a mutagenic hazard for humans.

Abstract  Cultured bronchial epithelial and fibroblastic cells from humans were used to study DNA damage and toxicity caused by formaldehyde. Formaldehyde caused the formation of cross-links between DNA and proteins, caused single-strand breaks in DNA, and inhibited the resealing of single-strand breaks produced by ionizing radiation. Formaldehyde also inhibited the unscheduled DNA synthesis that occurs after exposure of cells to ultraviolet irradiation or to benzo[a]pyrene diolexpoxide but at doses substantially higher than those required to inhibit the resealing of x-ray-induced single-strand breaks. Therefore, formaldehyde could exert its mutagenic and carcinogenic effects by both damaging DNA and inhibiting DNA repair.

Abstract  The alkaline elution technique was used to study repair of DNA damage caused by formaldehyde (HCHO) in human bronchial epithelial cells and fibroblasts, skin fibroblasts, and DNA excision repair-deficient skin fibroblasts from donors with xeroderma pigmentosum. Exposure of cells to HCHO resulted in DNA-protein cross-links (DPC) and DNA single-strand breaks (SSB) in all cell types. DPC were induced at similar levels and were also removed by all cell types, with a half removal time of 2 to 3 hr. HCHO caused more SSB in the normal cell types than in the xeroderma pigmentosum fibroblasts. However, in all cell types, including the xeroderma pigmentosum cells, HCHO-induced DNA SSB and DPC were removed at comparable rates. By excision repair of HCHO-induced DNA damage, normal cells generated SSB that were also readily repaired. HCHO was only moderately cytotoxic to normal bronchial epithelial cells and fibroblasts at concentrations that induced substantial DNA damage. HCHO enhanced the cytotoxicity of both ionizing radiation and N-methyl-N-nitrosourea in both cell types. The results indicate that most DPC caused by HCHO can be removed without the involvement of DNA excision repair. Furthermore, HCHO also directly causes DNA SSB as well as SSB generated indirectly during ultraviolet-type excision repair. These studies indicate the complexity of the HCHO-induced DNA damage and its repair and that HCHO may enhance the cytotoxicity of chemical and physical carcinogens in human cells.

Abstract  Cultured Chinese hamster V79 cells, a widely utilized model system in risk assessment of environmental agents, have been utilized to measure toxicity and mutagenicity of formaldehyde with or without previous exposure to either the alkylating agent N-nitroso-N-methylurea or to ionizing radiation. Each of these agents caused a dose-dependent decrease in colony forming efficiency and a parallel increase in 6-thioguanine resistant colonies. Significant mutant frequencies were induced by 0.3 up to 1 mM formaldehyde, 2 and 4 Gy of radiation and 0.2 and 0.5 mM N-nitroso-N-methylurea. Exposure of cells to ionizing radiation or N-nitroso-N-methylurea followed by submutagenic concentrations of formaldehyde potentiated both the cytotoxicity and the mutagenicity as compared with the corresponding separate effects caused by each of these agents. Taken together, these studies clearly demonstrate genotoxic effects in vitro of three recognized carcinogens, i.e. formaldehyde, N-nitroso-N-methylurea and ionizing radiation. Moreover, the synergies now demonstrated in regards to cytopathic consequences indicate interactive effects between formaldehyde and these agents, representing both a chemical and a physical carcinogen.

Abstract  The formation and development of initiated cells has been studied at the beginning of hepatocarcinogenesis. Rats received the genotoxic carcinogen N-nitrosomorpholine (NNM); placental glutathione S-transferase was used as a marker of initiated cells (G+ cells). Single G+ cells appeared within 24 h after NNM; their frequency increased steeply for approximately 2 weeks, then decreased and finally remained constant. G+ foci consisting of >/=2 G+ cells appeared successively after the single cells. Histological determination of DNA replication and apoptosis revealed that: the formation of single G+ cells may not depend on DNA replication of precursor cells; single G+ cells showed considerably lower DNA replication than G- normal hepatocytes; from the 2-cell stage onwards G+ foci displayed enhanced DNA replication and apoptosis. Data from histological sections were transformed into the third dimension by a new stereological method which considers the non-spherical shape of many G+ lesions. Rates of division and death of G+ cells and of formation and growth of G+ foci were estimated by a stochastic model: initially G+ clones appeared at a rate of 12 000 per day and liver until a maximal number of 176 000 (phase I) was reached; thereafter they declined to 134 000 (phase II); they then remained constant (phase III). Estimated division rates of G+ cells decreased from phase I to phase III, while the death rate increased in phase II, when every third G+ clone disappeared. As a result, at day 50 after NNM only 0.3% of G+ single cells had formed a clone containing >/=5 cells. In conclusion, experimental and computed parameters provide direct evidence that hepatocarcinogenesis evolves clonally and that initiated hepatocytes have a selective proliferation advantage, associated with an enhanced potential to undergo apoptosis. Thereby, depending on the conditions, initiated clones expand or become extinct. Extinction may lead to reversion of the biological effects of initiation.

Abstract  Methylene chloride was less mutagenic in Salmonella typhimurium TA100/NG-11 (glutathione-deficient) compared to TA100, indicating that glutathione is involved in the activation of methylene chloride to a mutagen in bacteria. In rodents, the pathway of methylene chloride metabolism utilizing glutathione produces formaldehyde via a postulated S-chloromethylglutathione conjugate (GSCH2Cl). Formaldehyde is known to cause DNA-protein cross-links, and GSCH2Cl may act as a monofunctional DNA alkylator by analogy with the glutathione conjugates of 1,2-dihaloalkanes. The lack of sensitivity of Salmonella TA100 towards formaldehyde (Schmid et al., Mutagenesis, 1 (1986) No. 6, 427-431) suggests that GSCH2Cl is responsible for methylene chloride mutagenicity in Salmonella. In Escherichia coli K12 (AB1157), formaldehyde was mutagenic only in the wild-type, a characteristic shared with cross-linking agents, whereas 1,2-dibromoethane (1,2-DBE) was more mutagenic in uvrA cells (AB1886). Methylene chloride, activated by S9 from mouse liver, was mutagenic only in wild-type cells, suggesting a mutagenic role for metabolically derived formaldehyde in E. coli. Mouse-liver S9 also enhanced the cell-killing effect of methylene chloride in the uvrA, and a recA/uvrA double mutant (AB2480) which is very sensitive to DNA damage. This pattern was consistent with formaldehyde damage. However, a mutagenic role in bacteria for the glutathione conjugate of methylene chloride cannot be ruled out by these E. coli experiments because S9 fractions did not increase 1,2-DBE mutagenicity, suggesting lack of cell wall penetration by this reactive species. Rat-liver S9 did not activate methylene chloride to a bacterial mutagen or enhance methylene chloride-induced cell-killing, which is consistent with the carcinogenicity difference between the species.

Abstract  Glutathione-S-transferase-mediated metabolism of methylene chloride (MC) generates S-chloromethylglutathione, which has the potential to react with DNA, and formaldehyde, which is a known mutagen. MC-induced mutations in the HPRT gene of Chinese hamster ovary cells have been sequenced and compared with the mutations induced by 1, 2-dibromoethane (1,2-DEB), which is known to act through a glutathione conjugate, and formaldehyde. All three compounds induced primarily point mutations, with a small number of insertion and deletion events. The most common point mutations induced by MC were GC-->AT transitions (4/8), with two GC-->CG transversions and two AT-->TA transversions. This pattern of mutations showed greater similarity with 1,2-DBE, where the dominant point mutations were GC-->AT transitions (7/9), than formaldehyde, where all mutations were single base transversions and 5/6 occurred from AT base pairs. The mutation sequence results for MC suggest that S-chloromethylglutathione plays a major role in MC mutagenesis, with only a limited contribution from formaldehyde. The involvement of a glutathione (GSH) conjugate in MC mutagenicity would be analogous to the well-characterized pathway of activation of 1,2-DBE.

Abstract  Pregnant hamsters were treated by topical application of formaldehyde solution on day 8, 9, 10 or 11 of gestation. Fetuses recovered on day 15 were weighed, measured, and examined for teratogenic effects of formaldehyde exposure. The resorption rate was increased in the treated groups, but formaldehyde treatment did not significantly affect weight or length, nor did any malformations which could be related to treatment appear. It was concluded that fetal risk due to maternal topical exposure to formaldehyde is minimal in this model system.

Abstract  Blood-cell cancers (leukaemias, lymphomas and myeloma) are a very diverse group of neoplasms derived from a variety of stem cells at different hierarchical levels of haemopoietic and lymphoid cell development. This biological heterogeneity is likely to be associated with a variety of different etiological mechanisms. Correspondingly, a large number of inherited normal allelic variations might be expected to contribute to risk. Leukaemias alone have more than 200 different acquired (non-constitutive) molecular abnormalities but some are much more prevalent than others and are associated with biological subtypes with distinctive clinical or prognostic features. Balanced chromosome translocations are very common, together with simple gains or losses of chromosomes. Gene deletions and mutations are also relatively common, especially in more advanced disease. In several types of leukaemia and lymphoma, a transition from benign to malignant status can be tracked together with concurrent accrual of additional molecular abnormalities (e.g. chronic myeloid leukaemia evolving into blast crisis and follicular lymphoma becoming diffuse). The covert preclinical natural history of paediatric leukaemia has been revealed by 'back-tracking' using chromosomal translocation-gene-rated fusion gene sequences as clone-specific stable, specific and sensitive markers. Studies in identical twins, in archived neonatal blood spots of patients and in normal newborn cord bloods all support the contention that chromosomal translocations often initiate leukaemia in utero. Twin concordance rates (and animal modelling) suggest that further secondary genetic changes and exposures postnatally are, however, critical and this is endorsed by the finding that leukaemic fusion genes are present in normal newborn infants at a rate that far exceeds the cumulative risk of leukaemia. The natural history of leukaemic subtypes provides a useful framework for molecular epidemiological studies and significant advances have been made in this respect with infant and childhood acute lymphoblastic leukaemia.

Abstract  Topic 1. What conclusions can be drawn from the available experimental data relative to the carcinogenicity/ genotoxicity of formaldehyde? Are there data from studies that permit projections to be made about potential human responses? a. What role does the cytotoxicity of formaldehyde play in its carcinogenicity in experimental animals? b. What is the significance of benign tumors and potential preneoplastic lesions in the carcinogenic response in rats exposed to formaldehyde by inhalation? c. What do genotoxicity studies tell us about the potential of formaldehyde to be an initiator or promoter for carcinogenesis or a mutagen in somatic or germ cells? d. What nonneoplastic changes occur when experimental animals and man are exposed to formaldehyde? What is the health significance of these changes? Topic 2. What critical questions remain to be answered?