Assessment in rats of the reproductive toxicity of gasoline from a gasoline vapor recovery unit.

Gasoline (CAS 86290-81-5) is one of the world's largest volume commercial products. Although numerous toxicology studies have been conducted, the potential for reproductive toxicity has not been directly assessed. Accordingly, a two-generation reproductive toxicity study in rats was conducted to provide base data for hazard assessment and risk characterization. The test material, vapor recovery unit gasoline (68514-15-8), is the volatile fraction of formulated gasoline and the material with which humans are most likely to come in contact. The study was of standard design. Exposures were by inhalation at target concentrations of 5000, 10 000, and 20 000 mg/m(3). The highest exposure concentration was approximately 50% of the lower explosive limit and several orders of magnitude above anticipated exposure during refueling. There were no treatment-related clinical or systemic effects in the parental animals, and no microscopic changes other than hyaline droplet nephropathy in the kidneys of the male rats. None of the reproductive parameters were affected, and there were no deleterious effects on offspring survival and growth. The potential for endocrine modulation was also assessed by analysis of sperm count and quality as well as time to onset of developmental landmarks. No toxicologically important differences were found. Therefore, the NOAEL for reproductive toxicity in this study was > or =20 000 mg/m(3). The only systemic effects, in the kidneys of the male rats, were consistent with an alpha-2 u-globulin-mediated process. This is a male rat-specific effect and not relevant to human health risk assessment.

Life-long absence of sexual drive in a woman associated with 5-dihydrotestosterone deficiency.

A case of a woman who presented with life-long absence of sexual drive is reported. Although her history contained psychological factors that might have been etiologic in her presentation, she had not responded to sex therapy or cognitive-behavior psychotherapy undertaken at other clinics. When seen by the author, she was found to have poorly developed external genitalia. The only abnormality discovered on endocrinological evaluation was a reduced level of 5 dihydrotestosterone. Treatment with dihydrotestosterone gel applied to her vulva generated sexual drive and her ability to become sexually aroused.

Self-assessment of morbidity following radical hysterectomy for cervical cancer.

The aim of this study was to assess the magnitude of the morbidity following radical surgery for early stage cervical cancer. We performed a retrospective survey of all women who had undergone a radical hysterectomy and lymphadenectomy between the months of July 1995 and December 1996 inclusive at either the Royal Marsden or St George's Hospital (n =38), using a detailed questionnaire on bladder, ano-rectal and sexual function, both before and after treatment. Sixteen women (44.4%) received adjuvant radiotherapy. The mean interval between surgery and inquiry was 16.4% months (range 8-25 months). The mean age at the time of surgery was 40.5 years. Thirty-six out of 38 women contacted responded (94.7%). Overall 33 women (91.7%) reported new bladder, ano-rectal or sexual symptoms. Complaints of urinary incontinence, particularly of urge incontinence, and of voiding difficulties increased significantly after surgery (P <0.05). However, only 5.3% of women had sought treatment. Tenesmus increased significantly (P <0.05), while increases in diarrhoea and faecal incontinence were not statistically significant (P =0.051). Although 12.9% of women stated an improvement in their sex lives, 54.8% thought that their sex life was worse after treatment, and 12.9% of women had ceased sexual activity altogether. Of women of childbearing age 53.8% felt adversely affected by their loss of fertility. Bladder, ano-rectal and sexual symptoms are very common following radical hysterectomy for cervical cancer, with adverse effect on quality of life, and persist into the second year after treatment.

Management of vulval pain--whose responsibility?

Vulval pain can be acute or chronic. Usually patients present to their general practitioner when the pain is acute but, when specialist advice is required, vulval pain can present a real dilemma over to whom to refer patients. Genitourinary medicine, gynaecology, dermatology and sexual dysfunction clinics all play an important part in the holistic management of this symptom. Consultation in a sympathetic environment with appropriate investigations and collaboration between different disciplines may provide a diagnosis and management.

A comprehensive evaluation of the mechanism of skin tumorigenesis by straight-run and cracked petroleum middle distillates.

The role of skin irritation and other factors on the tumorigenic activity of petroleum middle distillates (PMDs) in mice was examined in a comprehensive research program. The program culminated in a 2-year dermal carcinogenicity study which compared the effects of equal weekly doses of irritating and nonirritating PMDs. Modified Ames mutagenicity studies and three- to seven-ring polycyclic aromatic compound (PAC) analyses indicated that the mutagenic activity of PMDs was correlated to PAC content. In subchronic and subacute studies, PMDs produced marked skin irritation which was ameliorated if the test samples were diluted in mineral oil. The reduction in irritation level was not a result of reduced dermal absorption. Straight-run kerosine (SRK), straight-run gas oil (SRGO), and catalytically cracked light cycle oil (LCO) were evaluated in the dermal carcinogenicity study. Test materials were applied either undiluted (2x/week) or as 28.5% (7x/week) or 50% (4x/week) concentrations in mineral oil for a total weekly dose of 100 microliters PMD per animal. All three materials produced moderate to marked skin irritation and increased tumor frequency when applied undiluted. When diluted, the irritant effects of SRK and SRGO, which contain low levels of PACs, were ameliorated, and there were no significant increases in tumors relative to controls. LCO, containing 8.7% three- to seven-ring PACs, increased tumor frequency when diluted, even when skin irritation was limited. These data indicate that the tumorigenic activity of straight-run MDs is likely a consequence of a nongenotoxic process, associated with frequent cell damage and repair. PMDs which contain low levels of three- to seven-ring PACs are unlikely to cause tumors in the absence of prolonged skin irritation. In addition, genotoxic mechanisms may also contribute to tumor formation for other PMDs containing higher levels of PACs, e.g., products blended with cracked stocks.

Impotence and its non-surgical management.

Impotence is a common symptom which can cause considerable distress to both the sufferer and his partner. The use of pharmacotherapy to improve erectile function will continue to increase as safe and effective drugs are developed. However, restoring erectile function should not be the only treatment objective. It is also essential to address personal and emotional factors in the sufferer, conflicts in his relationship with his partner, and sexual problems in his partner, all of which may be instrumental in causing or maintaining the presenting impotence. We advocate a combined approach with appropriate medical treatment and sex and couple therapy.

Perceived carer attitudes to alcohol dependent patients.

Negative attitudes among carers towards people with alcohol-related problems have been reported in many studies. However, few studies have examined whether these attitudes are perceived by patients during face to face contact with healthcare professionals when receiving inpatient treatment. A sample of 26 discharged patients completed a 37-item questionnaire following treatment for alcohol problems. The Likert scale was used to measure whether patients felt that the attitude under investigation existed in the caring environment. The findings indicated that negative attitudes reported in other studies were not perceived by patients during inpatient treatment. Some barriers to treatment effectiveness such as prognostic pessimism were detected by the patients. Many upheld the view that the only goal of treatment adopted by staff was that of total abstinence. There is an increasing need to obtain feedback from patients who have received inpatient care. Greater flexibility and creativity in the care of the alcohol dependent person needs to be explored rather than the maintenance of a prescriptive approach.

Yohimbine in the treatment of erectile disorder.

Yohimbine is an alkaloid derived mainly from the bark of the African tree, Pausinystalia yohimbe. Although many pharmacological properties of yohimbine have been described, at the plasma concentration attained at recommended dosages in man the predominant activity is antagonism of alpha 2-adrenoceptors. For more than 70 years yohimbine has been used as a treatment for male and female sexual difficulties. It has enjoyed a reputation as an aphrodisiac although no effect on sexual drive in humans has been adequately demonstrated. Yohimbine has been evaluated in the management of erectile disorder by means of placebo-controlled but often poorly designed trials. It does appear to have a modest therapeutic benefit over placebo, particularly in essentially psychogenic erectile disorder, and is generally well tolerated. Yohimbine is not licensed in the UK.

Identification of immunotoxic effects of chemicals and assessment of their relevance to man.

Immunotoxicity is defined as the adverse effects of foreign substances (xenobiotics) on the immune system. Two types of effects are possible: immunosuppression (which may result in an increased susceptibility to infection or to the development of tumours) and immunopotentiation (which may manifest as an allergy or as autoimmunity). There is, as yet, little evidence that well controlled occupational exposure to industrial chemicals has led to clinically significant immunosuppression. In contrast, a number of industrial chemicals have been shown to cause immunopotentiation in exposed populations, producing occupational asthma and contact dermatitis and possibly autoimmunity. In experimental models, immunosuppression (usually assessed by in vivo or in vitro immune function tests) has been induced by a wide range of chemicals but there are a few reports of the immunosuppression leading directly to an increased susceptibility to infection or to the development of tumours. Predictive experimental models are available for type IV allergic reactions, but the identification of chemicals that have a potential to cause other types of allergy or autoimmune reactions requires further research and the development and validation of new animal models. It is considered that routine subacute and chronic toxicity studies should include a full gross and histopathological assessment of the lymphoid organs to more accurately detect the potential of a chemical to cause immunotoxicity. Should such studies indicate that a substance has affected the immune system directly, an assessment of overall immune competence and function tests may be necessary using dose levels below those which cause frank toxicity. However, precise interpretation of immune function tests in terms of their relevance to human health requires an improved understanding of the extent of the functional reserve of the immune system. A strategy for assessing immunotoxicity in exposed human populations demonstrates a need for reliable clinical assessment, accurate medical record-keeping, an environmental and biological monitoring for levels of contaminating chemicals and the judicious use of well-validated immune function tests.

A comparative study of the effects of ranitidine and cimetidine on carbohydrate tolerance, growth hormone secretion and the hypothalamic-pituitary-gonadal axis in man.

The effect of chronic oral administration of cimetidine (1 g per day) and ranitidine (300 mg per day) on plasma levels of prolactin (PRL), testosterone, dihydrotestosterone (DHT), luteinizing hormone (LH), follicle stimulating hormone (FSH), sex hormone binding globulin (SHBG) and human growth hormone was compared in 2 groups of male patients who presented with dyspeptic symptoms. Eight were treated with ranitidine and 9 with cimetidine for 4 weeks. The glucose and insulin response to a 100 g oral glucose load was also assessed. Cimetidine treatment resulted in a significant increase in plasma testosterone levels which was not found in the ranitidine group. No significant change occurred in PRL, LH, FSH, SHBG, DHT and growth hormone. There was no evidence of a significant alteration in carbohydrate metabolism.

Coital rates, age and method of contraception: results of a BJSM pilot questionnaire survey.

PIP: A study was undertaken to determine whether differences in coital rates exist among the users of different contraceptive methods. Data about the frequency of intercourse, age of respondent, and method of contraception were collected from a questionnaire and included in the December 1983 edition of the "British Journal of Sexual Medicine." Analysis of variance was used to analyze the data, and a Box Cox plot revealed that the square root transformation was the most appropriate. The following contrasts were considered: oral contraception (OC) and IUD versus sheath; OC, IUD, sheath, and diaphragm versus female sterilization and vasectomy; OC versus diaphragm; and sheath versus diaphragm. The age of the female partner was used in the statistical model to assess whether the differences in coital frequency between the 2 elements in the contrasts depended on age. There was no interaction between any of the contrasts and age at the 5% level. This means that the difference between the individual elements of a contrast does not depend on the age of the female partner. Paired age of female and coital frequency data were available for 435 respondents. The frequency decreased with increasing age. The reported frequency of coitus ranged from less than once a month to 37 times a month. There was a significant decrease in the coital rate as the age of the female partner increased at the 0.1% level. When the contrasts were considered, there was a significant difference in coital frequency between the OC and IUD group and the sheath group and between the sheath and diaphragm group, but there was no difference between the OC and diaphragm group. There also was no significant difference in coital frequency among the OC, IUD, sheath, and diaphragm groups and female sterilization and vasectomy group. The study results confirm a significant decreasing relationship between frequency of intercourse and the age of the female partner. Duration of marriage has been shown to be a more important factor in determining coital rates than the age of either spouse, but this was not inquired about in this study. Respondents who used the sheath had a lower mean coital rate than those who used OC, IUD, or the diaphragm.^ieng

Response of the upper respiratory tract of the rat to white spirit vapour.

The threshold limit value (TLV) adopted by industry for white spirit is that of Stoddard's solvent and is currently set at 100 ppm (525 mg/m3). Exposure of rats to atmospheres containing an average of 214 mg/m3, 4 h/day, for 4 consecutive days resulted in irritation of the membranes lining the upper respiratory tract but only minimal signs of lung injury. Histopathological changes were observed in the nasal cavity, trachea and larynx and included loss of cilia, mucous and basal cell hyperplasia and squamous metaplasia. These results suggest that in man exposure to white spirit at or around the TLV may result in irritation of the upper respiratory tract.

Effect of beta-adrenoceptor antagonists on prevalence of peripheral vascular symptoms in hypertensive patients.

1 Eight hundred patients were approached by questionnaire to give details of side effects of their antihypertensive medications. The response rate was 72.8%. The percentage of those questioned who were taking beta-adrenoceptor antagonists at the time was 54.6%. 2 Raynaud's phenomenon (P less than 0.05) and complaints of cold extremities (P less than 0.001) were significantly more frequent in women than in men, 74.8% of women complained of cold extremities. 3 Exposure to beta-adrenoceptor antagonists did not increase the prevalence of Raynaud's phenomenon in either men or women in the study, but did increase the prevalence of cold extremities in men (P less than 0.001). Propranolol, labetalol, oxprenolol and possibly atenolol were likely to produce such side effects. Smoking and the addition of vasodilators did not alter the effect of beta-adrenoceptor blockers on peripheral vascular symptoms. Complaints of cold extremities were not associated with an excess of complaints of other side effects.