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PubMed1994

Follow-up of a group of workers intoxicated with 4,4'-methylenedianiline.

4,4'-Methylenedianiline (MDA), an aromatic amine, is a known human hepatotoxin and an animal carcinogen but there is little information regarding its chronic effects in humans. Between 1967 and 1976, 10 workers at a plant in Ontario that used MDA as an epoxy hardener developed acute jaundice. We followed this group from the date of intoxication through to the end of 1991 for cancer incidence by matching with the Ontario Cancer Registry. To date, one cancer, a pathologically confirmed bladder cancer has developed (expected number based on provincial incidence rates: 0.64 for all cancers, 0.05 for bladder cancer). This finding may be important because bladder cancer was a site of interest a priori; bladder cancers have been observed in two other occupationally exposed groups (significantly higher than expected in one of these); in the National Toxicology Program bioassay, urinary bladder tumors occurred in exposed animals but not in controls; and MDA has structural similarity to known human bladder carcinogens such as benzidine.

Acute Disease↗

PubMed2005

Transdifferentiation of rat hepatocytes into biliary cells after bile duct ligation and toxic biliary injury.

Rats with chimeric livers were generated by using the protocol of injecting hepatocytes from dipeptidyl peptidase IV (DPPIV)-positive donors into retrorsine-treated DPPIV-negative recipients subjected to partial hepatectomy. Rats with established chimeric livers were subjected to bile duct ligation, with or without pretreatment with the biliary toxin methylene diamiline (DAPM). Ductules bearing the donor hepatocyte marker DPPIV were seen at 30 days after bile duct ligation. The frequency of the ductules derived from the donor hepatocytes was dramatically enhanced (36-fold) by the pretreatment with DAPM. In conclusion, our results show that hepatocytes can function as facultative stem cells and rescue the biliary epithelium during repair from injury when its proliferative capacity is being compromised.

Aniline Compounds↗

PubMed1993

Phase studies of a urethane model compound and polyether macroglycols by infrared spectroscopy and the relationship between eutectic composition of soft segment and blood compatibility.

The binary mixtures of a urethane model compound, diethyl 4,4'-methylenebis(N-phenylcarbamate) (MDU), and various polyether macroglycols have been investigated mainly by infrared (IR) spectroscopy. The mixtures of macroglycol and MDU showed two C=O bands (free C=O at higher wave number, hydrogen bonded C=O at lower wave number), and the intensity of free C=O increased while that of hydrogen bonded C=O decreased linearly with increasing molar ratio of macroglycol/MDU. The slope of the increase or decrease suddenly changed at the specific molar ratio around the eutectic composition. The eutectic molar composition for PTMO1000/MDU was determined as 1.15 or 1.1 by differential scanning calorimetry (DSC) or infrared (IR) studies while that for PTMO3000/MDU as 0.345 or 0.55 by DSC or IR, respectively. The eutectic compositions for other sets were determined by IR studies as follows: PEO1000/MDU, 0.4; PEO3000/MDU, 0.16; PPO1000/MDU, 1.4; PPO3000/MDU, 0.45. The number of ethylene oxide, tetramethylene oxide, and propylene oxide units to form a eutectic with MDU calculated from these values were 15-20, 10-11, and 23-24, respectively. The similar DSC or IR changes were observed in the various kinds of polyurethanes such as MDI/BD, MDI/PTMO/BD, and MDI/PTMO polymers. The relationship between the eutectic compositions of soft segments (MDI/macroglycol) and the ideal Mn of the macroglycols in blood compatibility of segmented polyurethanes are discussed.

Benzyl Compounds↗

PubMed2006

Identification of metabolites of 4,4'-methylenedianiline in vascular smooth muscle cells by liquid chromatography-electrospray tandem mass spectrometry.

A capillary liquid chromatography-electrospray tandem mass spectrometry (LC-ES-MS/MS) method was developed for the identification of metabolites of 4,4'-methylenedianiline (diaminodiphenyl methane, (DAPM)) derived from exposure of vascular smooth muscle cells (VSMC) to this compound. The use of precolumn concentration and column switching techniques prior to reversed-phase liquid chromatography coupled online to ES-MS enabled the separation and detection of low-level DAPM and its metabolites in the exposed cell samples. The employed LC-ES-MS method, and further LC-ES-MS/MS analysis enabled the structural assignments for two DAPM metabolites from vascular smooth muscle cells: N-acetyl methylenedianiline (N-acetyl-DAPM) and N,N'-diacetyl methylenedianiline (N,N'-diacetyl-DAPM).

Aniline Compounds↗

PubMed2002

Acute toxicity, mutagenicity, and estrogenicity of bisphenol-A and other bisphenols.

Although abundant data are available on the toxicity of bisphenol-A (2,2-bis (4-hydroxydiphenyl)propane; BPA), little is known about the toxicities of the structurally similar compounds, namely bisphenols (BPs). A variety of BPs were examined for their acute toxicity against Daphnia magna, mutagenicity, and estrogenic activity using the Daphtoxkit (Creasel Ltd.), the umu test system, and the yeast two-hybrid system, respectively, in comparison with BPA. BPA was moderately toxic to D. magna (48-h EC50 was 10 mg/l) according to the current U.S. EPA acute toxicity evaluation standard, and it was weakly estrogenic with 5 orders of magnitude lower activity than that of the natural estrogen 17 beta-estradiol in the yeast screen, while no mutagenicity was observed. All seven BPs tested here showed moderate to slight acute toxicity, no mutagenicity, and weak estrogenic activity as well as BPA. Some of the BPs showed considerably higher estrogenic activity than BPA, and others exhibited much lower activity. Among the tested BPs, two compounds, i.e., bisphenol-S (bis(4-hydroxydiphenyl)sulfone) and bis(4-hydroxyphenyl)sulfide, have never been reported for their estrogenic activity previously.

Animals↗

PubMed1996

MDA in plasma as a biomarker of exposure to pyrolysed MDI-based polyurethane: correlations with estimated cumulative dose and genotype for N-acetylation.

The object of this study was to investigate whether exposure of pipe-layers to thermal degradation products of diphenylmethane diisocyanate (MDI) could be assessed by analysing 4,4-methylenedianiline (MDA) in hydrolysed plasma and urine, and whether the genotype for N-acetylation affected these biomarker levels. Blood and urine samples were drawn from 30-pipe-layers who had been welding polyurethane (PUR) insulated pipes during the preceding 3 months. MDA in hydrolysed plasma and urine was determined with a gas chromatography-mass spectrometry technique, and genotype for N-acetylation was analysed with a polymerase chain reaction technique. MDA in plasma was detected in 18 of the 30 pipe-layers. Their plasma concentrations of MDA varied from 0.05 to 8.48 micrograms/l. There was a significant negative correlation between time since last welding of PUR-insulated pipes and P-MDA (rs = 0.50, P = 0.005). There was also a significant positive correlation between the estimated number of welded PUR-insulated pipes during the preceding 3 months and P-MDA (rs = 0.68, P = < 0.001). No significant association between genotype of N-acetylation and P-MDA was observed in a multiple regression analysis when adjustment was made for the estimated cumulative exposure to thermal degradation products of MDI. MDA in urine was detected in only four of the 30 pipe-layers. These four subjects had been welding PUR pipes on the same day as the sampling, or on the day before. The present results indicate the spot plasma samples analysed for MDA may give a rather good estimate of exposure to MDI during the preceding months. P-MDA, but not U-MDA, therefore seems to be a useful biomarker of long-term exposure to MDI. The individual N-acetylation capacity did not affect the plasma levels of MDA.

Acetylation↗

PubMed1995

Biomonitoring of 4,4'-methylene dianiline by measurement in hydrolysed urine and plasma after epicutaneous exposure in humans.

Five healthy volunteers were dermally exposed for 1 h to 0.75-2.25 mumol 4,4'-methylene dianiline (MDA) dissolved in isopropanol, by use of a patch-test technique. Determination of MDA remaining in the patch units after exposure showed that a median of 28% (range 25-29%) was absorbed. By analysis of hydrolysed plasma, an initial accumulation of MDA could be shown, and then a decline. MDA was also detected in hydrolysed urine. The maximum rate of MDA excretion in urine was found 6-11 h after the onset of exposure. Within two subjects studied at three doses, the urinary excretion was proportional to the exposure. The elimination half-lives (elim-t1/2) in plasma and urine had medians of 13 and 7 h, respectively. In eight out of nine exposures, the elim-t1/2 was longer in plasma than in urine. Slow acetylation seemed to be associated with short elim-t1/2 in urine. The median of total MDA amount excreted in urine during 48 h, was 33 nmol for the five subjects exposed to 0.75 mumol, which corresponded to roughly 16% (range 2%-26%) of the absorbed dose while only a limited number of individuals were studied, the data still indicated that MDA in hydrolysed plasma or urine can be used for biological monitoring of occupational dermal exposure. However, the individual variation must be taken into account. Sampling should preferably be made several hours post shift. Urine is preferred before plasma at low exposures, because of its higher concentrations of MDA.

Acetylation↗

PubMed2005

Thyroid hormone receptor-beta-selective agonist GC-24 spares skeletal muscle type I to II fiber shift.

Triiodothyronine (T3) is known to play a key role in the function of several tissues/organs via the thyroid hormone receptor isoforms alpha (TRalpha) and beta (TRbeta). We have investigated the effects of GC-24, a novel synthetic TRbeta-selective compound, on skeletal muscle fiber-type determination, cross-sectional area, and gene expression in rat skeletal muscles. For fiber typing, cross sections of soleus and extensor digitorum longus (EDL) muscles were stained for myosin ATPase activity at various pHs. Serum T3, T4, and cholesterol levels were also determined. Analysis of highly T3-responsive genes, viz., myosin heavy chain IIa (MHCIIa) and sarcoendoplasmic reticulum adenosine triphosphatase (SERCA1), was performed by quantitative real-time polymerase chain reaction. Equimolar doses of T3 and GC-24 had a similar cholesterol-lowering effect. T3, but not GC-24, decreased fiber type I and increased fiber type II abundance in soleus and EDL muscles. Conversely, in EDL, both T3 and GC-24 decreased the mean cross-sectional area of type I fibers. MHCIIa gene expression was reduced (approximately 50%) by T3 and unchanged by GC-24. SERCA1 gene expression was strongly induced by T3 (approximately 20-fold) and mildly induced by GC-24 (approximately two-fold). These results show that GC-24 does not significantly alter the composition of skeletal muscle fiber type and further strengthens the putative use of GC compounds as therapeutic agents.

Acetates↗

PubMed1997

Modulation of taurine levels in the rat liver alters methylene dianiline hepatotoxicity.

Methylene dianiline (DAPM) causes hepatic damage and bile duct necrosis in rats. This has been detected histologically and biochemically. The toxicity was dose related over the range 0-100 mg/kg but the dose response relationship showed a maximum at about 75-100 mg/kg. This was true for both histopathology and biochemical parameters of liver dysfunction. When animals were depleted of taurine using beta-alanine pretreatment, the toxicity of DAPM was increased. Conversely treatment of rats with taurine, significantly attenuated the rise in alanine transaminase (ALT). However depletion of taurine with guanidinoethanesulphonate (GES) attenuated rises in both transaminases. It is concluded that taurine may play a role in the toxicity of DAPM but that GES, although depleting taurine as does beta-alanine, causes additional effects such as increasing glutathione (GSH), perhaps leading to protection.

Aniline Compounds↗

PubMed1986

Carcinogenesis studies of 4,4'-methylenedianiline dihydrochloride given in drinking water to F344/N rats and B6C3F1 mice.

Carcinogenesis studies of 4,4'-methylenedianiline dihydrochloride (98.6% pure) were conducted by administering this chemical in the drinking water of F344/N rats and B6C3F1 mice. Groups of 50 rats and 50 mice of each sex received drinking water containing 150 or 300 ppm 4,4'-methylenedianiline dihydrochloride (dosage expressed as the free base) for 103 wk. Groups of 50 rats and 50 mice of each sex, given drinking water adjusted with 0.1 N HCl to the pH (3.7) of the 300-ppm formulation, served as controls. Survival was comparable among groups except for male mice receiving the 300-ppm dose of 4,4'-methylenedianiline dihydrochloride; survival in that group was lower than that in controls. Mean body weight was reduced in 300-ppm-dose female rats and 300-ppm-dose male and female mice compared to controls. Water consumption was reduced in a dose-related manner in both sexes of rats. No compound-related clinical effects were observed. Under the conditions of these studies, there was clear evidence of carcinogenicity for F344/N rats and for B6C3F1 mice in that 4,4'-methylenedianiline dihydrochloride caused increased incidences of (1) follicular-cell carcinomas of the thyroid gland (controls, 0/49; low dose, 0/47; high dose, 7/48, 15%; p less than or equal to 0.012) and neoplastic nodules of the liver (controls, 1/50, 2%; low dose, 12/50, 24%; high dose, 25/50, 50%; p less than or equal to 0.001) in male rats, (2) follicular-cell adenomas (controls, 0/47; low dose, 2/47, 4%; high dose, 17/48, 35%; p less than or equal to 0.001) and C-cell adenomas (controls, 0/47; low dose, 3/47, 6%; high dose, 6/48, 13% p less than or equal to 0.029) of the thyroid gland in female rats, (3) follicular-cell adenomas of the thyroid gland (controls, 0/47; low dose, 3/49, 6%; high dose, 16/49, 33%; p less than or equal to 0.001), carcinomas of the liver (controls, 10/49, 20%; low dose, 33/50, 66%; high dose, 29/50, 58%; p less than or equal to 0.001), and pheochromocytomas of the adrenal gland in male mice (controls, 2/48, 4%; low dose, 12/49, 24%; high dose, 14/49, 29%; p less than or equal to 0.001), and (4) follicular-cell adenomas of the thyroid gland (controls, 0/50; low dose, 1/47, 2%; high dose, 13/50, 26%; p less than or equal to 0.001), carcinomas (controls, 1/50, 2%; low dose, 6/50, 12%; high dose, 11/50, 22%; p less than or equal to 0.002) and adenomas (controls, 3/50, 6%; low dose, 9/50, 18%; high dose, 12/50, 24%.(ABSTRACT TRUNCATED AT 400 WORDS)

Aniline Compounds↗

PubMed2006

The heat shock protein inhibitor KNK437 induces neurite outgrowth in PC12 cells.

The nervous system is highly sensitive to various environmental stresses, such as ischemia. Stress response mechanisms that result in neuroprotection, including the induction of heat shock proteins (HSP), are not well understood. We examined the effect of KNK437, a compound that inhibits the synthesis of inducible heat shock proteins, on neuronal differentiation in rat pheochromocytoma PC12 cells. KNK437 decreased the expression of HSP70, and induced the neurite outgrowth of PC12 cells in the absence of stress stimulation, although with lower efficacy than nerve growth factor (NGF). Neurite outgrowth stimulated by KNK437 and NGF was blocked by inhibitors of ERK mitogen-activated protein (MAP) kinase, p38 MAP kinase, and glycogen synthase kinase 3beta signaling pathways. NGF, and not KNK437, induced acetylcholine esterase (AChE) activity, a functional differentiation marker, indicating that KNK437 utilizes a mechanism distinct from that of NGF. KNK437 enhanced the activity of low dose NGF treatment on neurite outgrowth induction and ERK phosphorylation in PC12 cells, a finding that identifies KNK437 as a possible nerve regeneration agent. This compound may be a useful tool for the investigation of neuronal differentiation and neuroprotection against environmental stress.

Acetylcholinesterase↗

PubMed2006

Developmental exposure to environmental estrogens alters anxiety and spatial memory in female mice.

Humans and wildlife are exposed to numerous anthropogenic drugs and pollutants. Many of these compounds are hormonally active, and recent evidence suggests that the presence of these endocrine disruptors permanently alters normal development and physiology in a variety of vertebrate species. Here, we report on the effects of developmental exposure to two common estrogenic pollutants, bisphenol A and ethinyl estradiol on sexually dimorphic, non-reproductive behavior. Mice (Mus musculus domesticus) were exposed to environmentally relevant levels of these chemicals (2 and 200 microg/kg/day for bisphenol A and 5 microg/kg/day for ethinyl estradiol) throughout prenatal and early postnatal development. As adults, the animals were observed in a variety of tests measuring sexually dimorphic behaviors including short-term spatial memory (in a radial-arm maze and a Barnes maze) and anxiety (in an elevated-plus maze and a light/dark preference chamber). Developmental exposure to ethinyl estradiol was found to masculinize behavior in all of the assays used. Bisphenol A increased anxious behavior in a dose-dependent fashion but had no effect on spatial memory. These results indicate that non-reproductive, sexually dimorphic behavior is sensitive to endocrine disruption. In addition, these experiments suggest that both humans and wildlife are being exposed to levels of these endocrine disrupting compounds that are sufficient to disrupt the development of the nervous system and that may have permanent consequences on sexually dimorphic behaviors.

Analysis of Variance↗

PubMed2006

The effects of caffeine, dextroamphetamine, and modafinil on humor appreciation during sleep deprivation.

STUDY OBJECTIVES: Sleep loss consistently impairs performance on measures of alertness, vigilance, and response speed, but its effects on higher-order executive functions are not well delineated. Similarly, whereas deficits in arousal and vigilance can be temporarily countered by the use of several different stimulant medications, it is not clear how these compounds affect complex cognitive processes in sleep-deprived individuals. DESIGN: We evaluated the effects of double-blind administration of 3 stimulant medications or placebo on the ability to appreciate humor in visual (cartoons) or verbal (headlines) stimuli presented on a computer screen following 49.5 hours of sleep deprivation. SETTING: In-residence sleep-laboratory facility at the Walter Reed Army Institute of Research. PARTICIPANTS: Fifty-four healthy adults (29 men, 24 women), ranging in age from 18 to 36 years. INTERVENTIONS: Each participant was randomly assigned to 1 of 3 stimulant medication groups, including caffeine, 600 mg, n = 12; modafinil, 400 mg, n = 11; dextroamphetamine, 20 mg, n = 16; or placebo, n = 14. MEASUREMENTS AND RESULTS: Humor appreciation for cartoon stimuli was enhanced by modafinil relative to both placebo and caffeine, but there was no effect of any stimulant medication on the appreciation of verbal humor during sleep loss. In contrast, all 3 stimulants improved psychomotor response speed, whereas only caffeine and dextroamphetamine improved ratings of subjective sleepiness. CONCLUSIONS: Findings suggest that, despite similar alerting and vigilance-promoting effects, these 3 compounds have significantly different effects on those highly complex cognitive abilities mediated by the pre-frontal cortex.

Adolescent↗

PubMed2002

DNA damage induced by 4,4'-methylenedianiline in primary cultures of hepatocytes and thyreocytes from rats and humans.

4,4'-Methylenedianiline (MDA), an aromatic amine used in various industrial processes and previously found to induce tumor development in liver and thyroid of mice and rats, was evaluated for its DNA-damaging activity in primary cultures of hepatocytes and thyreocytes from rat and human donors. After exposure for 4 and 20 h to MDA concentrations ranging from 10 to 180 microM, a statistically significant increase in the frequency of DNA lesions was revealed by the Comet assay in primary hepatocytes and thyreocytes from donors of both species, the response being dose dependent up to 56-100 microM MDA. DNA fragmentation was more marked after 4 than after 20 h exposure in all four cell types. DNA was damaged to a lesser extent in human hepatocytes and thyreocytes than in corresponding rat cells and in both species in hepatocytes than in thyreocytes. In both rat and human hepatocytes a 20-h exposure to the same MDA concentrations elicited a modest amount of DNA repair synthesis, as evaluated by autoradiography. Evidence of a partial reduction of DNA damage, and therefore of only partial DNA repair, was observed in rat hepatocytes and in rat and human thyreocytes incubated for 16 h in MDA-free medium after a 4-h MDA treatment. A 4-h exposure to 56, 100, and 180 microM MDA did not induce DNA lesions in primary cultures of cells from three rat organs, kidney, urinary bladder mucosa, and brain, which are resistant to MDA carcinogenic activity. Under the same experimental conditions any evidence of DNA damage was absent in primary kidney and urinary bladder cells from human donors. Taken as a whole the results of this work indicate that MDA is specifically activated to DNA-damaging reactive species by hepatocytes and thyreocytes in both rats and humans and thus suggest that liver and thyroid might be the targets of the carcinogenic activity of MDA also in humans.

Aged↗

PubMed1998

Investigation of the induction of DNA double-strand breaks by methylenediphenyl-4-4'-diisocyanate in cultured human lung epithelial cells.

The question was addressed whether methylenediphenyl-4,4'-diisocyanate (MDI), a bifunctional electrophile, can induce DNA double-strand breaks (DSB) by repair of interstrand DNA crosslinks or whether DSB are the result of cell death. Cultured human lung epithelial cells (A549) were treated with MDI, methylene-4,4'-dianiline (MDA; a potential hydrolysis product of MDI), the nitrogen mustard melphalan, and the detergent Triton X-100. All chemicals were dissolved in ethylene glycol dimethyl ether which was added to a cell monolayer covered with phosphate-buffered saline. After 2 h, the treatment solution was exchanged against medium, and 8, 24, and 72 h after treatment initiation, the induction of DNA double-strand breaks was assessed by pulsed-field gel electrophoresis. At the same time, the viability was determined with the MTT test (intracellular reduction of the tetrazolium dye MTT). At the 8-h time point, 1 and 10 microM melphalan induced DSB without concomitant effect on cell viability. With all other chemicals, the dose-response curves for DNA fragmentation and viability were mirror images. Approximate 50% lethal concentrations were 200, 3000, and 100 microM for MDI, MDA, and Triton X-100, respectively. For these chemicals, the observed DSB were the consequence of extragenomic damage in the course of cell death rather than of an interaction with DNA. The mechanistic difference of melphalan was supported by analysis of nuclear morphology. Apoptotic bodies were observed only after melphalan treatment, whereas MDI and Triton X-100 produced only irregular clumping of chromatin (72-h time point). DNA fragment length analysis showed a time-independent pattern, with sizes between 1 and 4 Mbp for melphalan, while MDI, and Triton X-100 induced smaller DNA fragments in a time-dependent manner. It is concluded that DSB observed in cells treated with MDI are unlikely the result of DNA crosslink formation.

Aniline Compounds↗

PubMed1995

4,4'-Methylenedianiline in hydrolysed serum and urine from a worker exposed to thermal degradation products of methylene diphenyl diisocyanate elastomers.

A 45-year-old mechanic employed in blowing hot air (350 degrees-600 degrees C) onto the surface of a polyurethane methylene diphenyl diisocyanate (MDI) conveyer belt developed dyspnoea, rhinoconjunctivitis and fever. The illness was suggestive of an MDI-associated illness, compatible with both immediate hypersensitivity and a complement-mediated immune-complex reaction. In his serum there were specific IgG and IgE antibodies against MDI and other isocyanates, and high values of circulating immune complexes. The patient's blood and urine samples were analysed for the presence of 4,4'-methylenedianiline (MDA) in hydrolysed urine and plasma. MDA was derivatized to amides using pentafluoropropionic acid anhydride (PFPA). Gas chromatography-mass spectrometry determinations were made monitoring the (M-20; M = molecular mass) fragments from the MDA-PFPA and the [2H2]MDA-PFPA derivative. The first urine sample was obtained 22 h and the last sample 114 h after start of exposure. The urine concentrations of MDA were corrected for creatinine. The half-time of MDA was 70-80 h. The first serum sample was obtained 19 h and the last sample 1967 days after the start of exposure. The half-time was 21 days, which suggests the presence of MDI/MDA plasma protein adducts in the exposed worker.

Aniline Compounds↗

PubMed2004

Percutaneous penetration and genotoxicity of 4,4'-methylenedianiline through rat and human skin in vitro.

4,4'-Methylenedianiline (MDA) is a primary aromatic amine used in the plastics industry and is classified by the International Agency for Research on Cancer as an animal carcinogen and possible human carcinogen. In order to estimate human exposure it is useful to determine percutaneous penetration. Previous studies have suggested that both rat and human skin were permeable to MDA, with greater penetration being seen through human skin. In this study no significant difference was seen between the percutaneous penetration of MDA through human or rat skin for three different treatment levels: 0.01, 0.1 and 1mg per skin membrane (0.32 cm(2)). The apparent dermal flux was calculated as 0.7 +/- 0.3 and 10.1 +/- 2.0 microg/cm(2)/h for the 0.01 and 0.1mg treatments, respectively. The permeability constant K(p) was estimated at 1.8 x 10(-3) cm/h and the lag time at 3.5 +/- 0.5 h. MDA absorbed into the skin was found to be bioavailable. Experiments also showed that after application of 0.1mg MDA, 4% penetrated through latex and nitrile gloves, respectively. The potential genotoxicity of MDA in human skin was assessed by DNA (32)P-postlabelling; levels of DNA adducts were detected, following the treatment and penetration of 1mg MDA.

Aniline Compounds↗

PubMed1995

Formation and elution of toxic compounds from sterilized medical products: methylenedianiline formation in polyurethane.

The formation of a toxic and carcinogenic compound, methylenedianiline (MDA), in sterilized medical use polyurethane (PU) is discussed. Due to good biocompatibility and biostability, PU is widely used for blood-containing devices. There are two types of PU currently available for medical use. One is chain-extended thermoplastic PU, the other is thermosetting PU used for potting material connecting fibers and modules in artificial dialyzers and plasma separators. Both gamma-ray irradiation and autoclave sterilization are predominantly used for the sterilization of these devices. MDA formation in sterilized PUs by gamma-ray irradiation and by autoclave treatment is compared. The Delany clause in the USA prohibits the manufacture of medical devices producing any toxic compound during fabrication and sterilization, therefore, the formation and elution of MDA and other toxic compounds should be seriously considered. Although MDA formation at a concentration of a few to a few hundred ppb in autoclaved chain-extended thermoplastic PU has been reported, there have been no papers describing MDA formation in autoclaved thermosetting PU potting material, or describing MDA formation in gamma-ray irradiated chain-extended thermoplastic PU and thermosetting PU. We elected to determine whether MDA was in fact produced in Pus sterilized by gamma-ray irradiation or by autoclave sterilization. Our objective was to estimate the risk factor to the human patients or recipient. Our conclusion is to confirm which sterilization of gamma-ray or autoclave is more appropriate. No formation of MDA was observed in autoclaved thermosetting PU potting material at 121 degrees C for 60 min. A few ppm of MDA was formed in irradiated potting material. MDA formation increased with increasing irradiation doses. MDA formed in irradiated potting material at 2.5 Mrad (less than one ppm) is not a significant risk to the recipient. The estimated cancer causing risk factor when absorbing one mg MDA/kg body weight/day is 0.29. Twenty-nine persons per 100 persons exhibit a cancer potential. More importantly, our experimental evidence indicated that serum extracts from irradiated potting material contained unknown compounds other than MDA. The presence of these compounds is considerably more significant and toxic. When tested, these compounds proved to be mutagenic in the absence of metabolic activity, thus promoting a need to identify and study further. Compounds indicating mutagenicity increased with increasing irradiation. Small amounts of mutagenic compounds were determined in extract from autoclaved potting material, smaller than that by gamma-ray irradiation. Therefore, autoclave sterilization is more appropriate, providing materials can withstand the process.(ABSTRACT TRUNCATED AT 400 WORDS)

Aniline Compounds↗