Evaluation of the hazards of industrial exposure to tricresyl phosphate: a review and interpretation of the literature.

Commercial tricresyl phosphate (TCP) is a heterogeneous mixture of isomers and aryl phosphate congeners, known for many years to induce delayed neurotoxicity (OPIDN) in humans and experimental animals. In the past the isomer tri-o-cresyl phosphate (TOCP) was thought to be the component primarily responsible for OPIDN. It is now clear that other constituents, particularly the mono-o-esters, are not only neurotoxic but also may be more potent than pure TOCP. As a generality, the toxicity potential of a particular brand of TCP is related to its content of o-phenolic residues, whereby the maximal potential is reached when o-phenolics are 33% of the mix. Historically, human TCP toxicity has resulted from inadvertent or intentional contamination of foodstuffs or beverages. TCP products with high ortho-residues synthesized by older manufacturing methods were involved in most of these cases, and were likely much more neurotoxic milligram for milligram than TOCP. Because of the great variability of TCP products, there are no conventional workplace exposure standards. Based upon data from the hen and cat, estimated human safe exposure rates for pure TOCP are estimated to be 2.5 mg/kg for a single dose, and 0.13 mg/kg/d for repetitive exposures. These levels may also be applied to TCP when o-methyl-phenyl, o-ethyl-phenyl, and o-xylenyl components are appropriately limited during manufacture such that the TCP product is less neurotoxic than TOCP. There have been relatively few reports of toxicity associated with the manufacture or use of TCP in commerce and industry. Low vapor pressures of the constituents preclude the presence of significant quantities of TCP vapor in the atmosphere. A lubricant or other formulation containing TCP may appear in the air as a mist. By these criteria the U.S. Petroleum Oil Mist exposure standard is protective when the formulation contains 4% or less of low ortho-TCP. Exposure calculations indicate that estimated safe levels are not likely to be exceeded in the well-regulated workplace. If it is of short duration, even a heavy fog of oil particulate may not exceed the 8-h-average inhalation exposure standard. Modern manufacturing practices tend to minimize the ortho content and thus the toxicity of TCP. Because individual TCP brands and synthesis methods vary, manufacturers should be consulted concerning the properties of their individual products.

Parenting from a distance: the effects of paternal characteristics on contact between nonresidential fathers and their children.

Changes in marital and fertility behavior have influenced the role of father for many men. We use data from the first two waves of the National Survey of Families and Households to examine various sociodemographic, situational, and attitudinal characteristics that might influence the degree of contact between nonresidential fathers and their minor children. We tap two different dimensions of distance parenting and find that although several variables influence both visiting and talking on the telephone or writing letters, some factors (the presence of multiple children in a household) predict visiting only, while others (child's age and gender) predict only verbal/written contact. Similarly, some of the life-course decisions made by fathers appear to crowd out their involvement with nonresidential children, whereas other decisions reinforce their parenting behavior.

Outcome after invasive local recurrence in patients with ductal carcinoma in situ of the breast.

PURPOSE: To detail the outcome, in terms of local recurrence, local invasive recurrence, distant recurrence, and breast cancer mortality for patients previously treated for ductal carcinoma in situ (DCIS). PATIENTS AND METHODS: Clinical, pathologic, and outcome data were collected prospectively for 707 patients with DCIS accrued from 1972 through June 1997. RESULTS: There were 74 local recurrences; 39 were noninvasive (DCIS) and 35 were invasive. Fifty-one percent of patients with invasive recurrences presented with stage 1 disease; the remainder presented with more advanced disease. Invasive local recurrence after mastectomy was a rare event that occurred in 0.8% of patients. Invasive recurrence after breast preservation was more common and occurred in 7.4% of patients. The 8-year probability of breast cancer mortality after breast preservation was 2.1%, a number that is likely to increase with longer follow-up. The 8-year breast cancer-specific mortality and distant-disease probability for the subgroup of 74 patients with locally recurrent disease was 8.8% and 20.8%, respectively. If only the 35 invasive recurrences are considered as events, the 8-year breast cancer-specific mortality and distant-disease probability was 14.4% and 27.1%, respectively. CONCLUSION: Invasive local recurrence after breast-preservation treatment for patients with DCIS is a serious event that converts patients with previous stage 0 disease to patients with disease that ranges from stage I to stage IV. These results, however, indicate that most DCIS patients with local recurrence can be salvaged.

Predictors of axillary lymph node metastases in patients with T1 breast carcinoma.

BACKGROUND: Axillary lymph node metastases (ALNM) are the most important predictor of survival in patients with T1 breast carcinoma. Due to a relatively low incidence of axillary metastasis in tumors < or = 2 cm, the role of axillary lymph node dissection for these patients has been questioned. The purpose of this study was to determine the association between the incidence of ALNM and 11 clinical/pathologic factors by univariate and multivariate analysis. METHODS: The authors reviewed data from 918 patients with T1 breast carcinoma who underwent level I/II axillary dissection between 1979 and July 1995. The association between the incidence of ALNM and 11 clinical/pathologic factors (size, lymph/vascular invasion, nuclear grade, S-phase, ploidy, palpability, age, estrogen receptor status, progesterone receptor status, HER-2/neu, and histology) was analyzed by univariate and, when significant, by multivariate analysis. RESULTS: Approximately 23% of the 918 patients with T1 breast carcinoma had ALNM. Multivariate analysis identified four factors as independent predictors of ALNM: lymph/vascular invasion (P < 0.0001), tumor palpability (P < 0.0001), nuclear grade (P = 0.0004), and tumor size (P = 0.01). Among the 117 patients with nonpalpable, nonhigh grade tumors < or = 1 cm without lymph/vascular invasion, the incidence of ALNM was only 3%. However, the 43 patients with T1c tumors with all 3 additional risk factors had a 49% incidence of ALNM. CONCLUSIONS: Clinical and pathologic features of the primary tumor can be used to estimate the risk of ALNM in patients with T1 breast carcinoma. Such a risk assessment might facilitate appropriate management. Routine axillary dissection can be omitted in patients at minimal risk of ALNM, if the treatment decision is not influenced by lymph node status. Axillary lymph node dissection should be performed routinely for all patients with lesions > 1 cm. [See editorial counterpoint on pages 1856-61 and reply to counterpoint on pages 1862-4, this issue.]

Results from a multidisciplinary breast center. Analysis of disease discovered.

This study was undertaken to report the clinical, pathologic, and outcome data of our nonrandomized series of patients with nonpalpable breast cancer and to understand better the differences between patients with palpable and nonpalpable lesions, particularly those patients aged 49 and younger. The clinical, pathologic, recurrence, and survival data from 560 patients with nonpalpable breast carcinomas found by mammography and wire-directed breast biopsy were compared with similar data from 1640 patients who presented with palpable breast cancer (see Table 3). All node dissections in patients with noninvasive disease were negative. In patients with invasive breast cancer, the chances of axillary node involvement increased as lesions increased in size. When patients were grouped by tumor size, nodal involvement was more likely for palpable than nonpalpable lesions. The 10-year disease-free survival rate probability for patients with nonpalpable invasive cancer was 81% compared with 65% for patients with palpable invasive cancer. The 10-year breast cancer-specific survival rate (including deaths only from carcinoma of the breast) was 91% versus 73%, whereas the 10-year overall survival (rate including deaths from any cause) was 79% for nonpalpable invasive cancer versus 68% for patients with palpable invasive cancer (all P values < 0.001) (see Table 6). Patients under age 50 with nonpalpable invasive cancer fared just as well as older patients with nonpalpable invasive cancer; both had 10-year breast cancer-specific survival rates of 94% (see Table 8). However, biopsy of nonpalpable lesions in patients aged 49 and younger was only half as likely to reveal cancer than biopsy of nonpalpable lesions in patients aged 50 and older (17% versus 32%, P < 0.0001) (see Table 7). When cancer was found in younger women, it was more likely to be noninvasive. Wire-directed breast biopsy of nonpalpable mammographically suspicious areas yields a subgroup of breast cancer patients with a lower probability of recurrence and a higher probability of survival at 10 years when compared with patients who present with palpable breast cancer.

A prognostic index for ductal carcinoma in situ of the breast.

BACKGROUND: There is controversy and confusion regarding therapy for patients with ductal carcinoma in situ (DCIS) of the breast. The Van Nuys Prognostic Index (VNPI) was developed to aid in the complex treatment selection process. METHODS: The VNPI combines three significant predictors of local recurrence: tumor size, margin width, and pathologic classification. Scores of 1 (best) to 3 (worst) were assigned for each of the 3 predictors and then totaled to give an overall VNPI score ranging from 3 to 9. Three hundred thirty-three patients with pure DCIS treated with breast preservation (195 by excision only and 138 by excision plus radiation therapy) were studied with detection of local recurrence as the end point. RESULTS: There was no statistical difference in the 8 year local recurrence free survival in patients with VNPI scores of 3 or 4, regardless of whether or not radiation therapy was used (100% vs. 97%; P = not significant). Patients with VNPI scores of 5, 6, or 7 received a statistically significant 17% local recurrence free survival benefit when treated with radiation therapy (85% vs. 68%; P = 0.017). Patients with scores of 8 or 9, although showing the greatest relative benefit from radiation therapy, experienced local recurrence rates in excess of 60% at 8 years. CONCLUSIONS: DCIS patients with VNPI scores of 3 or 4 can be considered for treatment with excision only. Patients with intermediate scores (5, 6, or 7) show a 17% decrease in local recurrence rates with radiation therapy. Patients with VNPI scores of 8 or 9 exhibit extremely high local recurrence rates, regardless of irradiation, and should be considered for mastectomy.

Malignant seeding of the needle track during stereotaxic core needle breast biopsy.

Early reports demonstrated the diagnostic advantage of large-core (14-gauge) biopsy over fine-needle aspiration biopsy of nonpalpable lesions of the breast without apparent significant increase in morbidity. A case of malignant seeding of the needle track after a large-core biopsy of a mucinous carcinoma of the breast is documented. The potential for increased risk of tract seeding of malignancy must be considered.

Systemic toxicity from subchronic dermal exposure, chemical characterization, and dermal penetration of catalytically cracked clarified slurry oil.

Clarified slurry oil (CSO), the heavy residual fraction from the fluidized catalytic cracker, was applied to the shaven backs of groups of 10 male and 10 female Sprague-Dawley rats 5 days/week for 13 weeks at doses of 8, 30, 125, or 500 mg/kg/day, and to another group for 2 weeks at doses of 2000 mg/kg/day. The rats were fitted with cardboard Elizabethan collars to minimize the ingestion of the test material, which was applied undiluted and remained uncovered on the skin. A similar group of rats served as controls; they were treated in the same manner except that no CSO was applied to their skin. There was a dose-related mortality and depression of body weight gain in the rats treated with CSO at doses of 30 mg/kg/day or greater; none of the rats dosed at 2000 mg/kg/day survived more than 2 weeks. The primary target organs of CSO toxicity were the liver, thymus, and bone marrow. The effects on the liver included increased weight (250% at 500 mg/kg/day), cholangiolitis, diffuse liver cell degeneration and hypertrophy, necrosis, fibrosis, decreased serum glucose, increased levels of alkaline phosphatase, aspartate aminotransferase, alanine amino transferase, bilirubin, and triglycerides. The thymus was found to be small and upon microscopic examination to be atrophic or hypoplastic. Erythroid hypoplasia was found in the bone marrow of some of the rats dosed at 30 mg/kg/day and increased in severity with increasing dose. The erythroid hypoplasia was accompanied by a dose-related anemia. Even in the rats dosed at 8 mg/kg/day, very slight abnormalities in the bile ducts were observed upon microscopic examination of the liver. Chromatographic separation and analyses demonstrated that CSO contains about 58% 3- to 5-ring polycyclic aromatic hydrocarbons (PAHs) and approximately 8-10% carbazole derivatives. In vitro and in vivo skin penetration studies demonstrated that the carbazole materials penetrate through the skin to a considerable extent (about 44%); less penetration was observed with 2- or 3-ring (8-13%) or 5-ring PAHs (3%).

Alpha interferon in human pregnancy.

The concentration of interferon-alpha was measured by a specific two-site immunoradiometric assay in a variety of fluids and tissues collected during human pregnancy. Maternal blood and blood and tissues from non-pregnant adults contained little or no interferon-alpha. Fetal blood, fetal organs, placenta, membranes, amniotic fluid and decidua all contained significant and roughly equivalent amounts ranging from 1.1 to 10 u/ml (or per g of tissue). These findings demonstrate that the fetus and its immediate surroundings are permeated with interferon. It is suggested that this may play a role in regulation of the maternal-fetal graft relation.

Subchronic inhalation toxicity of benzene in rats and mice.

A subchronic inhalation toxicity study of benzene was conducted in CD-1 mice and Sprague-Dawley rats. Four groups of animals consisting of 150 mice and 50 rats/sex each were exposed to concentrations of 1, 10, 30, and 300 ppm benzene vapor, 6 hours/day, 5 days/week, for 13 weeks. Additional groups of mice and rats, of equal size, were exposed under similar conditions to filtered air and served as control groups. Thirty mice and 10 rats/sex in each group were sacrificed after 7, 14, 28, 56, and 91 days of treatment. Criteria used to evaluate exposure-related effects included behavior, body weights, organ weights, clinical pathology, gross pathology, and histopathology. Fifty animals per sex of each species were exposed concurrently for cytogenetic studies. In addition, blood serum was obtained for immunological assays. The results of these two studies will be reported separately. No consistent exposure-related trends were seen in the clinical observations and body weight data. Exposure-related clinical pathology changes were seen in the high-level (300 ppm) animals of both species. In the mice, these changes included decreases in hematocrit, total hemoglobin, erythrocyte count, leukocyte count, platelet count, myeloid/erythroid ratios, and percentage of lymphocytes. Mean cell volume, mean cell hemoglobin, glycerol lysis time, and the incidence and severity of red cell morphologic changes were increased in the mice. In the rats, decreased lymphocyte counts and a relative increase in neutrophil percentages were the only exposure-related clinical pathology alterations. Histopathologic changes were present in the thymus, bone marrow, lymph nodes, spleen, ovaries, and testes of mice exposed to 300 ppm and in most cases the incidence and severity of the lesions were greater in the males. These changes in the testes and ovaries at 300 ppm were also seen at lower concentrations, but they were of doubtful biological significance. In rats, the only exposure-related lesion consisted of slightly decreased femoral marrow cellularity in the animals exposed to 300 ppm.

The improved quality of life with the Kock continent ileostomy.

The conventional Brooke ileostomy is performed far more frequently than the Kock continent ileostomy. To determine the relative satisfaction with these operations, patients whose Brooke ileostomy had been converted to a Kock pouch were questioned about changes in their life-styles. Data were obtained from 80 patients who had worn an external appliance from 4 months to 33 years before the change-over to a Kock pouch. Improvement was reported in social activities (96.2%), athletic endeavors (87.5%), and sexual relations (76.2%). Patients spent less time caring for the stoma (92.5%) and wore street and beach attire with greater ease (97.5%). An average reduction of 75% was noted in ileostomy maintenance costs. The overall patient satisfaction with the Kock pouch was 98.7% despite an appreciable incidence of pouchitis and revisional operations. In our experience, the readier acceptance by patients of a continent internal reservoir over an external fecal-filled appliance has led to the performance of proctocolectomies for ulcerative colitis at an earlier stage of the disease.

Teratological evaluation of trimethyl phosphite in the rat.

Trimethyl phosphite (TMP) is an organophosphorus alkylating agent used primarily in the synthesis of organophosphate compounds. To evaluate teratogenic potential, TMP was administered by gavage to pregnant rats at rates of 16, 49, or 164 mg/kg/day, on gestation Days 6 through 15. Acetyl salicylic acid (250 mg/kg/day) was also administered to a group of rats as a positive control. Teratologic evaluation revealed gross fetal abnormalities, skeletal defects, and soft tissue defects at a dose rate of 164 mg/kg/day of trimethyl phosphite, but not at the two lesser rates. An increased frequency of fetal resorption was also observed at 164 mg/kg/day.

The Kock continent ileostomy.

Over a four and one-half year period, we have performed 100 Kock continent ileostomies with one nonpouch-related mortality. The large majority of these operations have been conversions of existing conventional ileostomies. Modifications in the surgical technique have gradually lowered the complication rate, and postoperative revisions are now required less frequently than for conventional ileostomies. Slippage of the nipple valve, the most troublesome complication of the Kock pouch operation, is currently seen in 4.1 per cent of the patients. Eversions of the nipple valve have been eliminated, and fistulas are now seen rarely. The so-called pouchitis, a postoperative complication noted in 10 per cent of the patients, is usually well controlled with metronidazole. Kock pouches performed upon patients in whom the original diagnosis was Crohn's ileocolitis have been followed by a high incidence of postoperative fistulas, but patients with Crohn's colitis have thus far fared as well as patients with ulcerative colitis. The over-all success rate for the Kock pouch operation in this series of patients is 97 per cent.

A biologic comparison of polyglactin 910 and polyglycolic acid synthetic absorbable sutures.

Two synthetic absorbable sutures were implanted in rats for a comparative evaluation of breaking strength, tissue reaction and absorption. Polyglactin 910 suture was stronger than polyglycolic acid suture in both sizes tested and at all time periods from zero to 35 days. Both suture types elicited minimal tissure response. Based upon histologic examination, virtually all remnants of the polyglactin 910 were absorbed by 90 days, while considerable quantities of polyglycolic acid persisted at 120 days. The difference in absorption rates was a highly significant feature of the comparative biologic profiles of the two suture materials.