Access to oncology consultation in a cancer cohort in northeastern Ontario.

BACKGROUND: To enhance cancer symptom management for residents of Sudbury-Manitoulin District, an ambulatory palliative clinic (pac) was established at the Northeast Cancer Centre of Health Sciences North. The pac is accessed from a medical or radiation oncology consultation. The primary purpose of the present population-based retrospective study was to estimate the percentage of cancer patients who died without ever having a medical or radiation oncology consultation. A secondary purpose was to determine factors associated with never having received one of those specialized consultations. METHODS: Administrative data was obtained through the Ontario Cancer Data Linkage Project. For each index case, we constructed a timeline, in days, of all Ontario Health Insurance Plan billing codes and associated service dates starting with the primary cancer diagnosis and ending with death. RESULTS: Within the 5-year study period (2004-2008), 6683 people in the area of interest with a valid record of primary cancer diagnosis died from any cause. Most (n = 5988, 89.6%) had 1 primary cancer diagnosis. For that subgroup, excluding those with a disease duration of 0 days (n = 67), about 18.4% (n = 1088) never had a consultation with a medical or radiation oncologist throughout their disease trajectory. Patients who were older or who resided in a rural area were significantly less likely to have had a consultation. CONCLUSIONS: Specific strategies directed toward older and rural patients might help to address this important access-to-care issue.

Toxicity and pharmacokinetics of 2-(2-dimethylaminoethoxy)ethanol following cutaneous dosing.

A 9-day repeated cutaneous toxicity study in the New Zealand White rabbit was conducted using 6-h occluded contact with 0 (water control), 50, 250 and 500 mg dimethylaminoethoxyethanol (DMEE)/kg. There were no clinical signs, and no effects on body weight, food consumption or serum chemistry. Hematological effects were limted to increased leukocyte count due to heterophil leukocytosis, increased platelet count, and decreased hemoglobin and hematocrit at the high dose. These findings are typical of the response of cutaneous inflammation. Histopathological findings were limited to the DMEE-treated skin, and consisted of acanthosis and ulcerative/necrotizing dermatitis. Thus, there was no evidence for cumulative percutaneous systemic toxicity for DMEE. The pharmacokinetics of DMEE was investigated in the Fischer 344 rats. Rats were given an intravenous dose of 15 or 150 mg/kg, or an occluded cutaneous dose of 150 mg/kg [14C]DMEE, and its fate was followed for 48-72 h. DMEE was readily absorbed through the skin (bioavailability=72-80%). Concentration in plasma rose steadily to a maximum at about 3.5 h after dosing, and then declined in a biphasic manner. 14C-DMEE-derived radioactivity was distributed throughout the body, with no apparent sequestration in any particular organ. The highest concentrations were observed in the kidney, liver and lung, and the lowest concentrations were found in the brain and fat. Urine was the major route of excretion, with minor amounts eliminated in the feces and as expired CO(2). The rate of excretion was moderate, with about 30% of the applied dose eliminated in the first 12 h, and by 72 h after dosing, less than 4% of the dose remained in the carcass. Unchanged DMEE was the principal component detected in the urine. This observation, together with the less than 1% of the dose excreted as CO(2), showed that metabolism was not an important process in the elimination of DMEE in the rat.

In vitro and in vivo genetic toxicology studies with diethylene glycol monohexyl ether.

Diethylene glycol monohexyl ether (DEGHE; CAS no. 112-59-4), an industrial chemical, was investigated for the potential to produce genotoxic effects using three in vitro and two in vivo tests. No mutagenic activity occurred in either the absence or presence of metabolic activation with a Salmonella typhimurium reverse assay using strains TA98, TA100, TA1535, TA1537 and TA1538. In a Chinese hamster ovary (CHO) forward gene mutation test (HGPRT locus) there was an increase in the mutation frequencies, which were relatively small compared with the solvent control values, somewhat inconsistent between duplicate cultures and occurred particularly in the presence of metabolic activation. Linear regression analysis indicated a marginally significant trend for dosage versus mutation frequency, suggesting that DEGHE was weakly positive in this test. A sister chromatid exchange test in CHO cells showed no significant dosage-related effects in the presence or absence of metabolic activation. A peripheral blood micronucleus test in mice by dosing with an intraperitoneal injection of DEGHE did not show any potential for DEGHE to increase the incidence of micronucleated polychromatophilic erythrocytes. In a first femoral bone marrow chromosome aberration test in the rat by peroral dosing, DEGHE did not cause any increase in aberrations for 12-h and 24-h samples with males and females or with females at 48-h sampling. However, with males at 48 h the two lowest doses showed an increased number of aberrations, but not at the high doses. A repeat study in males with a larger number of doses and 24-h and 48-h samples did not replicate this finding. It is concluded that DEGHE may have limited weak mutagenic activity in vitro but is devoid of clastogenic potential.

Subchronic peroral toxicity of triethylene glycol in the Fischer 344 rat.

Ethylene and diethylene glycols produce systemic toxicity, including nephrotoxicity, by acute and repeated po dosing. To determine the potential for triethylene glycol (TEG; CAS Number 112-27-61) to produce nephrotoxicity, or other organ/tissue injury, a subchronic (90-d) study was conducted by continuous inclusion of TEG in the diet of Fischer 344 rats. This was preceded by a probe 14-d study. For both studies the dietary concentrations were 0 ppm (control), 10,000, 20,000 or 50,000 ppm TEG, resulting in daily TEG consumptions in the 14-d study of 1132, 2311 or 5916 mg/kg with males, and 1177, 2411 or 6209 mg/kg with females. The corresponding values for the 90-d study were 748, 1522 or 3849 mg/kg (males), and 848, 1699 or 4360 mg/kg (females). In the 14-d study there were no mortalities or clinical signs, and no effects on body weight, hematology, serum chemistry, organ weights, and gross or microscopic pathology. Food consumption was increased at the high dosage. Urinalysis showed increased urine volume and decreased pH with high dose males and females, and increased volume with mid-dose males. In the subchronic study there was neither mortality nor signs of toxicity, and no dosage-related effects with serum chemistry, gross and microscopic pathology. Body weights were reduced during the dosing period with both males and females of the high dosage. Body weight gains were reduced at all dosages with males and females. No hematological effects were seen with females, but males of the mid- and high-dosage groups had slightly reduced erythrocyte count and hematocrit, and high-dose males had decreased hemoglobin concentration with increased mean corpuscular volume. These were considered to reflect a mild hemodilution related to the absorption of large TEG doses. Urinalysis showed dosage-related decreased pH, and increased urine volume mainly at the high dose. These were probably related to the renal excretion of absorbed TEG and/or metabolites. Kidney weight was increased for high-dose females, and increased relative (to body) weight of kidneys for males and females from the mid- and high-dose groups were observed, probably related to the renal excretion of the absorbed TEG and/or its metabolites. These findings indicate that the subchronic continuous po dosing of TEG to rats does not result in local or systemic specific organ or tissue toxicity. These findings contrast with the known repeated po toxicity, notably nephrotoxicity, produced by ethylene and diethylene glycols. Thus, TEG has significantly lesser potential for systemic toxicity by the po route than its lower molecular weight homologues.

A radiographic analysis of the relationship between the size and shape of the intercondylar notch and anterior cruciate ligament injury.

Notch-view radiographs were obtained from 108 persons with anterior cruciate ligament (ACL) injuries (55 women, 53 men) and 186 with intact ACL (94 women, 92 men). Notch width, femur width, and notch width index were determined from each of the 294 radiographs. The notch was also categorized as either A-shaped or non-A-shaped. Intrarater and interrater reliability ranged from 0.82 to 0.99 for notch width and femur width, respectively. Reliability within and between raters for the classification of notch shape ranged from 0.80 to 1.0. Notch width was significantly influenced by a 10 degree change in knee angle when repeated radiographs were taken. Femur width was not affected by knee angle across this range. Analysis revealed a higher proportion of A-shaped notches among women than men. However, notch shape was not related to injury status. Results showed a smaller notch width and notch width index in ACL-injured patients regardless of notch shape or gender. A-shaped notches were smaller than non-A-shaped notches regardless of injury status or gender. Both notch width and notch width index were found to be significant indicators of ACL injury. Knowledge of the shape of the notch added no useful information in differentiating patients based on injury status. Thus, regardless of gender, individuals who possess smaller notch dimensions appear to be at greater risk of injury than individuals with larger notches.

The acute toxicity and primary irritancy of glutaraldehyde solutions.

Glutaraldehyde (GA, CAS Number 110-30-8), an aliphatic dialdehyde, has a wide range of industrial, scientific, and medical applications. It is available in aqueous solutions, whose concentrations vary up to 50% (w/w) and from which there is a potential during use for skin and eye contact and exposure to the vapor. The acute toxicity and primary irritancy of a wide range of GA concentrations were investigated to determine the differential hazards for such solutions. The acute peroral toxicity in the rat, expressed as ml of solution dosed, was moderate for solutions of 5% and above (LD50 range 0.88-3.25 ml/kg) and generally varied little for solutions up to 50%. Solutions less than 5% GA were of slight toxicity (LD50 range 3.34-12.30 ml/kg for 1 and 2% solutions). When lethality was expressed as absolute amount of GA dosed (mg GA/kg), there was a reciprocal relationship between the concentration of GA solution dosed and LD50. This was confirmed in the mouse, which is more susceptible than the rat to acute peroral toxicity. The acute percutaneous toxicity of GA solutions to rabbits (24 h occlusion) was moderate (LD50 range 1.59-2.71 ml/kg) for 46 and 50% solutions, and slight for 25% GA solutions (8.80-16.00 ml/kg). At 15% and less, 16.0 ml/kg was not lethal. Exposures (4-8 h) of rats to saturated vapor atmospheres of GA generated dynamically or statistically at ambient temperature (17-25 C) produced only transient peripheral sensory irritant effects to the eyes and respiratory tract. In contrast, vapor atmosphere generated dynamically at elevated temperature (60 or 65 C) produce severe effects, including mortality (4-h LC50 range 23.5-44.3 ppm). Histopathology in rats that died included exposure concentration-related acute inflammation and necrosis in the nasal mucosa, larynx, trachea, and bronchi. Standard primary skin irritation tests in the rabbit indicated severe skin irritation and necrosis at 45 and 50% GA; necrosis occurred with 1 and 4 h contact at 50% and at 4 h with 45%. Inflammation was moderate at 25%, slight to moderate with 5 and 10% GA, minor at 2%, and threshold at 1%. Standard primary eye irritation tests showed 45% GA to produce severe conjunctival and corneal injury, which was persistent. At 2% GA corneal injury was mild, and at 5% marked. The lowest concentration producing corneal injury was 1.0%, and the no-effects concentration was 0.5%. The threshold for conjunctival effects was 0.2%, and the no-effects concentration 0.1%. At 1% GA, conjunctival hyperemia and chemosis were moderate to marked, and became more severe with higher GA concentrations. The results suggest potential acute handling hazards with various concentrations of GA solutions and indicate industrial hygiene considerations.

Toxicological, medical and industrial hygiene aspects of glutaraldehyde with particular reference to its biocidal use in cold sterilization procedures.

Aqueous solutions of > or =5% glutaraldehyde (GA) are of moderate acute peroral toxicity and those of < or =2% are of slight toxicity. By single sustained skin contact, aqueous GA solutions of > or =45% are of moderate acute percutaneous toxicity, those of 25% are of slight toxicity and those of or =5%. Primary skin irritation depends on the duration and contact site, occlusion and solvent. By sustained contact, the threshold for skin irritation is 1%, above which erythema and edema are dose related. With 45% and higher, skin corrosion may occur. There is a low incidence of skin sensitizing reactions, with an eliciting threshold of 0.5% aqueous GA. However, GA is neither phototoxic nor photosensitizing. Subchronic repeated exposure studies by the peroral route show only renal physiological compensatory effects, secondary to reduced water consumption. Repeated skin contact shows only minor skin irritant effects without systemic toxicity. By subchronic vapor exposure, effects are limited to the nasal mucosa at 1.0 ppm, with a no-effect concentration generally at 0.1 ppm. There is no evidence for systemic target organ or tissue toxicity by subchronic repeated exposure by any route. A chronic drinking water study showed an apparent increase, in females only, of large granular cell lymphocytic leukemia but this was not dosage related. This is most likely the result of a modifying effect on the factor(s) responsible for the expression of this commonly occurring rat neoplasm. A chronic (2-year) inhalation toxicity/oncogenicity study showed inflammatory changes in the anterior nasal cavity but no neoplasms or systemic toxicity. In vitro genotoxicity studies--bacterial mutagenicity, forward gene mutation (HGPRT and TK loci), sister chromatid exchange, chromosome aberration, UDS and DNA repair tests--have given variable results, ranging from no effect through to weak positive. In vivo genotoxicity studies--micronucleus, chromosome aberration, dominant lethal and Drosophila tests--generally have shown no activity but one mouse intraperitoneal study showed bone marrow cell chromosome aberrations. Developmental toxicity studies show GA not to be teratogenic, and a two-generation study showed no adverse reproductive effects. Percutaneous pharmacokinetic studies showed low skin penetration, with lowest values measured in vitro in rats and human skin. Overexposure of humans produces typical sensory irritant effects on the eye, skin and respiratory tract. Some reports have described an asthmatic-like reaction by overexposure to GA vapor. In most cases this resembles reactive airways dysfunction syndrome, and the role of immune mechanisms is uncertain. Local mucosal effects may occur if medical instruments or endoscopes are not adequately decontaminated. Protection of individuals from the potential adverse effects of GA exposure requires that there be adequate protection of the skin, eyes and respiratory tract. The airborne concentration of GA vapor should be kept below the recommended safe exposure level (e.g. the threshold limit value) by the use of engineering controls. Those who work with GA should, through a training program, be aware of the properties of GA, its potential adverse effects, how to handle the material safely and how to deal with accidental situations involving GA. If effects develop in exposed workers, the reasons should be determined immediately and corrective methods initiated. (c) 2001 John Wiley & Sons, Ltd.

Systemic toxicity from repeated cutaneous contact with 2,4-pentanedione.

2,4-Pentanedione (2,4 PD; CAS Number 123-54-6) is an industrial chemical with potential for skin contact. Repeated exposure studies by peroral and inhalation routes have shown central neurotoxicity and possible effects on the immune system. To determine the likelihood for systemic toxicity by cutaneous contact with 2,4-PD, a short-term repeated skin contact study was conducted in New Zealand white rabbits. The planned protocol was for dosing, with 0.5, 1.0 and 1.5 ml undiluted 2,4-PD by 6 h occlusive contact/d for 9 d; these were equivalent to dosages of 244, 975 and 1463 mg/kg/d. A dosage-related skin irritation was seen macroscopically and by light microscopy, which was minimal at the low dosage. Mortalities occurred at the mid (1/6 males, 3/6 females) and high dosages (5/12 males, 7/12 females), with deaths between the 2nd and 5th dosing day. In view of these mortalities and signs, dosing of the mid and high dose animals was discontinued, and survivors were kept to the end of the dosing period. Signs at the mid and high dosage included hypoactivity, tremors, convulsions, uncoordinated movements and prostration, and appeared between the 2nd and 4th dose. Body weight gain and food consumption were reduced for the mid and high dosage groups. Increased hemoglobin, hematocrit and erythrocyte counts may have been associated with dehydration, and increased heterophil count with cutaneous inflammation. Several serum biochemical changes reflected cutaneous irritation, and high creatine kinase activity was probably a consequence of convulsions. Immune effects included decreased lymphocyte counts and lymphoid necrosis in spleen and thymus. Central neuropathology in the mid and high dosages was seen as hemorrhages and neuronal degeneration, the latter principally in piriform cortex, globus pallidus and hippocampus. No peripheral neuropathy was present. 244 mg/kg/d was the no-effects dosage for systemic toxicity. This study confirmed a potential for systemic toxicity, principally central neurotoxicity, from percutaneous absorption of 2,4-PD.

Acute and repeated vapor exposure toxicology of 3-(methylthio)propionaldehyde.

Because of its vapor pressure (0.6 torr at 20 C) there is a potential for vapor exposure to 3-(methylthio)propionaldehyde (3-MTP) vapor. Liquid 3-MTP may contain trace amounts of acrolein (up to 0.1%), and therefore acrolein vapor may also be present. Acute exposure (24 min to 4 h) of rats to substantially saturated atmospheres of 3-MTP generated statically (measured concentrations of 261-951 ppm) resulted in marked ocular and respiratory irritancy followed by death. Deaths occurred either during exposure or a few days postexposure, depending on exposure time. Measured acrolein vapor concentrations in these static studies were 16.7-216 ppm. In contrast, when substantially saturated vapor atmospheres were generated dynamically (277-320 ppm 3-MTP) only minor transient signs of irritancy were present, and only 1/40 exposed animals died. Acrolein vapor concentrations ranged 0-6.8 ppm. These findings indicate that the toxicity associated with acute static exposures to 3-MTP vapor was due to accumulated acrolein vapor, and that 3-MTP per se has a low order of acute vapor inhalation toxicity. In a first 9-d repeated vapor exposure study (6 h/d) rats were exposed to 0, 23.6, 96.8 or 246.2 ppm 3-MTP vapor; the mean acrolein concentration was 1.34 ppm (range 1.08-1.72 ppm). There were no mortalities, but exposure concentration-related indications of toxicity were present. These included reduced body weights, hematology (increased lymphocytes), serum chemistry (reduced total protein and globulin), and respiratory tract histopathology. The latter consisted mainly of squamous metaplasia in the anterior nasal passages at all concentrations, being minimal at 23.6 ppm. At the high concentration there was also olfactory atrophy and squamous metaplasia in the larynx, trachea, and larger bronchi; 23.6 ppm was a threshold effect level. The respiratory tract histopathology was compatible with exposure to acrolein vapor. In a second 9-d study, rats were exposed to 0, 0.47, 4.99 or 50.5 ppm (6 h/d); no acrolein could be detected in the chamber air samples. There were no differences between the controls (air alone) and 3-MTP exposed animals with respect to signs, body weights, food consumption, hematology, serum chemistry, urinalysis, and gross and microscopic pathology. Without detectable acrolein vapor, 50.5 ppm 3-MTP was a no observable effects level.

Two-generation reproduction study by dosing with glutaraldehyde in the drinking water of CD rats.

Adult male and female CD rats (F0) were dosed with glutaraldehyde (GA; CAS number 111-30-8) in drinking water at concentrations of 0 (controls), 50, 250, or 1000 ppm for a 10-wk prebreed period and through mating, gestation, and lactation. Resultant F1 offspring, selected to be parents of the next generation, were continued on the same regime from prebreed through lactation. Twenty-eight parental animals per sex per generation for each dose group were evaluated for clinical signs, body weight (absolute and gain), and water and food consumption. The offspring were evaluated for survival and body weight to weaning. Necropsy and light microscopic examination of removed tissues were conducted in all F0 and F1 parents and in 10 offspring/sex/group/generation. Average daily consumptions of GA (as mean +/- SD) for the low, intermediate, and high concentrations were respectively 4.25 +/- 0.87, 17.50 +/- 4.16, and 69.07 +/- 14.58 mg/kg/d for F0 parental males, and 6.68 +/- 0.78, 28.28 +/- 4.09, and 98.37 +/- 11.71 mg/kg/d for F0 parental females. The corresponding values for the F1 parents were 4.53 +/- 1.02, 21.95 +/- 4.88, and 71.08 +/- 16.21 mg/kg/d for males and 6.72 +/- 0.84, 29.57 +/- 5.41, and 99.56 +/- 16.72 mg/kg/d for females. There were no effects on parental fertility and mating performance or on pup viability and litter size in any generation. No apparent treatment-related histopathology was seen in parents or offspring. Parental body weights and body weight gains were significantly reduced at 1000 ppm at a few isolated time periods, particularly during prebreed. Food consumption was significantly reduced at 1000 ppm for F0 and F1 parents during the prebreed and gestation periods, and at 250 ppm for F0 males during prebreed and gestation and F1 females during gestation and lactation. Water consumption by the F0 and F1 parents of the 250 at 1000 ppm groups was reduced throughout the prebreed period. At 1000 ppm, average litter weights were reduced over lactation d 21-28 for the F1 and F2 offspring. The no-observed-effect level (NOEL) for adult toxicity was 50 ppm and for offspring 250 ppm. There were no indications of reproductive toxicity, and the NOEL for this study was therefore > 1000 ppm.

Acute toxicity, primary irritancy, and genetic toxicity studies with 3-(methylthio)propionaldehyde.

Basic acute toxicity, primary irritancy, and genetic toxicity studies were conducted with 3-(methylthio)propionaldehyde (3-MTP). The acute rat peroral LD50 (with 95% confidence limits) for 3-MTP as a 25% (v/v) dilution in corn oil was 1.00 (0.59-1.70) ml/kg (males) and 1.68 (0.95-2.99) ml/kg (females); most deaths occurred 1.5 to 4 h postdosing. By 24-h occluded contact with undiluted 3-MTP, the rabbit acute percutaneous LD50 was 0.71 (0.43-1.15) ml/kg (males) and 0.79 (0.49-1.30) ml/kg (females): times to death ranged from 2 h to 2 d after the start of dosing. Exposure of rats to a statically generated saturated atmosphere killed all 5 males with a 40 min exposure and all 5 females with a 24 min exposure. In contrast, a 4-h exposure of rats to a dynamically generated saturated vapor atmosphere of 3-MTP did not produce any mortalities or signs of toxicity. A 4-hr occluded contact with 0.5 ml undiluted 3-MTP caused moderate to severe erythema and severe edema resolving by 7 to 17 d. Five/6 animals had necrosis apparent on removal of the occlusive dressing and persisting 10 to 17 d. On the rabbit eye, 0.1 ml undiluted 3-MTP produced moderate to severe corneal injury with iritis and moderate conjunctival inflammation which persisted 21 d in 3/6 animals; 0.01 ml caused moderate diffuse corneal injury and moderate conjunctival inflammation with healing by 7 d. 3-MTP did not produce mutagenic activity either in the absence or presence of metabolic activation with a Salmonella typhimurium reverse mutation assay using strains TA98, TA100, TA1535, TA1537 and TA1538. In a mouse lymphoma cell (L5178Y/tk +/-) assay, 3-MTP produced concentration-related increases in mutant colonies, both in the absence and presence of metabolic activation. Increases were mainly in the sigma (chromosomal damaging) colonies. In a mouse bone marrow micronucleus study, with vapor exposures to 37.4, 88.5 and 155.6 ppm for 1 h/d for 2 consecutive d, there were exposure concentration-related increases in micronucleated erythrocytes which were statically significant for male mice.

Developmental toxicity evaluation of rats dosed orally or cutaneously with octoxynol-9.

Pregnant CD rats were dosed cutaneously (530, 1600 or 4270 mg kg-1 day-1) or fed diets containing octoxynol-9 (70 or 340 mg kg-1 day-1) during the major period of organogenesis. Monitors for maternal toxicity included clinical observations, body weight, organ weight and food consumption. Fetuses were evaluated for body weight and for external, visceral and skeletal abnormalities. Maternal effects were noted in dams dosed cutaneously with 4270 mg kg-1 day-1 octoxynol-9, and included excoriation, exfoliation/desquamation in the area of treated skin, urine stains, perinasal encrustation and audible respiration. In addition, maternal weight gains were reduced during the dosing period. Octoxynol-9, dosed orally or cutaneously to gravid rats, had no effect on pregnancy performance but increased the incidences of a number of developmental abnormalities in the offspring. Most notable was the induction of supernumerary ribs arising from the lumbar and cervical regions. Other skeletal abnormalities included decreased incidences of poorly ossified supraoccipital and hyoid bones and zygomatic arches, suggesting an enhanced ossification in the neck and head regions. Increased incidences of two fetal visceral abnormalities, displaced tests in dams dosed orally with 340 mg kg-1 day-1 and atelectasis in dams dosed cutaneously with 1600 or 4270 mg kg-1 day-1 were also observed.

Subchronic inhalation toxicity of 3.5-microm diameter carbon fibers in rats.

No effects were seen when rats were exposed for 6 h day(-1), 5 days per week, for 16 weeks to an atmosphere of 20 mg m(-3) of carbon fibers (25 x 10(6) fibers m(-3)) and small amounts of fiber particulate resulting from preparation of the ultimate test material. The carbon fibers were made from polyacrylonitrile fiber. They were 3.5 microm in diameter and 72% were 10-60 microm long. Histopathological evaluations were made after each of 4, 8, 12 and 16 weeks of exposure and after 36 and 80 weeks of recovery. No effects due to the exposure were seen, as judged by clinical signs, body weight, organ weight, organ-body weight ratios, organ-brain weight ratios, gross and microscopic examination of internal organs, special stains of lung tissue for fibrous tissue, reticulin and fat and pulmonary function measurements. Non-fibrous particles were seen in the pulmonary lymphoid clearance system and in alveolar histiocytes (macrophages) at each histopathological evaluation period. Non-fibrous particles were seen in histiocytes in the mucociliary clearance system after 12 and 16 weeks of exposure. Fibers were seen in the nasal cavity at each histopathological examination. Fibers also occasionally were seen in tissue sections from the lower respiratory tract, but their exact location in life could not be determined. There was no indication of fibrosis.

Acute intravenous and inhalation pharmacokinetics of 2,4-pentanedione in the Fischer 344 rat.

2,4-Pentanedione (2,4-PD; CAS No. 123-54-6), an industrial chemical, was investigated for its comparative pharmacokinetics in male Fischer 344 rats by a single intravenous (i.v.) injection of (4.3, 43, 148.5, and 430 mg/kg), or a 6-hr nose-only inhalation exposure (400 ppm) to 14C-2,4-PD. For the i.v. route, the plasma concentration of 14C-2,4-PD-derived radioactivity declined in a biexponential fashion. The overall form of the 14C plasma concentration-time curves and derived pharmacokinetic parameters indicated that dose-linear kinetics occurred in the i.v. dose range 4.3-148.5 mg/kg, but not with 430 mg/kg. Metabolism of 2,4-PD was quite rapid as the concentration of unmetabolized 2,4-PD declined steadily to undetectable after 8 hr. 14C-2,4-PD derived radioactivity was eliminated mainly as 14CO2 and in urine. For the 4.3, 43 and 148.5 mg/kg doses 14CO2 elimination was relatively constant (36.8, 38.8 and 42.3% in 48 hr samples respectively) and greater than urinary excretion (17.9, 14.3 and 29.6%; 48 hr specimens). At 430 mg/kg i.v. there was a reversal of the excretion pattern, with urine 14C excretion (54.7%) becoming greater than that for 14CO2 (27.3%). Excretion in expired volatiles and feces was small. Radiochromatograms of urine showed free 2,4-PD in the 12 hr sample, together with 7 other metabolites. Free 2,4-PD and 6 of the metabolites decreased or were not detectable in a 24 or 48 hr urine sample, but one peak (retention 7.9 min) increased progressively to become the major fraction (97%). Nose-only exposure to 400 ppm 14C-2, 4-PD produced a mean decrease in breathing rate of 20.1%, which was constant and sustained throughout exposure, due to a lengthening of the expiratory phase of the respiratory cycle. 14C-2,4-PD was rapidly absorbed during the first 3 hr of exposure, then began to plateau, but did not reach a steady state. Postexposure elimination of 14C from plasma followed a biexponential form with a t1/2 for the terminal disposition phase of 30.72 hr. Plasma unmetabolized 2,4-PD was present throughout the whole of the exposure phase, but was significantly less than total 14C. Postexposure, plasma unmetabolized 2,4-PD declined rapidly to undetectable concentrations by 12 hr. Radiolabel excretion was approximately equivalent in urine (37.6%) and expired 14CO2 (36.3%). Urine radiochromatograms showed a minor 2,4-PD contaminant (0.6-5.9% over 48 hr), along with 7 other peaks probably representing metabolites. As with the 148.5 mg/kg i.v. dose, the major metabolite peak was at 7.8 min retention, increasing from 41.1% (12 hr) to 62.8% (48 hr). Immediately postexposure, radioactivity was present in all tissues examined, but on a concentration basis (microgram equiv/g) there was no preferential accumulation of 14C in any tissue or organ. On a total organ basis, highest contents were in liver and kidney, presumably related to the metabolism and excretion of 2,4-PD. By 48 hr postexposure, concentrations had decreased in all tissues except fat, presumably due to the lipophilicity of 14C residues. The profile of the plasma-time radioactivity curves, and the presence of residual radioactivity in tissues at 48 hr postexposure, suggests that a cumulative process could occur with frequent repeated exposures.

Investigations on the in vitro and in vivo genotoxic potential of 5-vinyl-2-norbornene.

5-Vinyl-2-norbornene (VNB: CAS no. 3048-64-4), an industrial chemical that produces hyaline droplet nephropathy in the male rat with associated alpha2u-globulin increases, was investigated in vitro and in vivo for its genotoxic potential. A Salmonella typhimurium reverse mutation assay (strains TA98, 100, 1535, 1537, 1538) was negative both without (dose range 0.003-0.3 mg per plate) and with (0.003-0.3 mg per plate) metabolic activation. A forward gene mutation test in Chinese Hamster Ovary (CHO) cells (HGPRT locus) did not show any significant concentration-related increases in mutation frequencies in the absence (0.01-0.1 mg ml[-1]) or presence (0.005-0.1 mg ml[-1]) of metabolic activation. In a sister chromatid exchange (SCE) test, VNB did not produce statistically significant or dose-related increases in the incidence of SCEs in the absence (0.02-0.06 mg ml[-1]) or presence (0.005-0.03 mg ml[-1]) of metabolic activation. A bone marrow chromosome aberration test was conducted in groups of 10 male and 10 female Sprague-Dawley rats exposed for 6 hr/day for 5 consecutive days to mean (+/- SD) VNB vapor concentrations of 0 (air control), 48.1 +/- 1.29, 146 +/- 9.2, or 336 +/- 8.5 ppm. Marrow was collected 6 and 24 hr after the final exposure. No statistically significant or dose-related increases in chromosomal aberrations occurred in the VNB-exposed animals. 5-Vinyl-2-norbornene did not show any potential for genotoxic activity with this in vitro-in vivo battery of tests.

Influence of alkalinization of glutaraldehyde biocidal solutions on acute toxicity, primary irritancy, and skin sensitization.

Aqueous glutaraldehyde (GA) is used at a concentration around 2% for the cold sterilization of endoscopy and dental instruments. Stock GA solution (pH 3.1-4.5) is alkalinized (pH 7.8-8.0) before use to optimize biocidal activity. The possible differential handling hazards between acidic unbuffered GA (UGA) and alkaline buffered GA (BGA) were compared for acute toxicity, primary irritancy and skin sensitizing potential using a 2.2% GA solution. Peroral LD5.0 values (with 95% confidence limits) in rats (combined sexes) were 3.45 (3.13-3.80) g/kg for UGA and 4.16 (3.13-5.52) g/kg for BGA; signs and gross pathology were similar. A 24-h occluded cutaneous application of 16.0 g/kg in the rabbit did not produce mortality; moderate skin irritancy was observed. No systemic effects occurred with UGA and only a few with BGA (unsteady gait, sluggishness, rapid breathing). Local skin irritation from a 4-h occluded contact with 0.5 ml was relatively minor and slightly more marked with BGA than UGA. Rats exposed to a statistically generated saturated vapor atmosphere for 6 h did not show any signs or gross pathology, and only slight weight loss occurred (UGA females). Rabbit eye irritation studies (0.1 ml) showed slightly more marked conjunctival reactions with BGA, but corneal injury was marked and persistent with BGA and only slight and transient with UGA. With 0.01 ml, no corneal injury occurred, but conjunctival reaction was more marked with UGA. A guinea pig maximization study showed UGA to produce a higher sensitizing index (68% at challenge, 32% at rechallenge) than BGA (30% at challenge, 5% at rechallenge). Severity indices at challenge was also higher for UGA [0.84 (24 h), 0.47 (48 h)] than BGA [0.45 (24 h), 0.18 (48 h)]. Both UGA and BGA have generally similar acute toxicity and skin irritancy; BGA has greater corneal injuring potential, and UGA has a greater skin sensitizing potential.