Breast-feeding exposure of infants to selected pesticides: a public health viewpoint.

In this paper, we provide an overview of the public health implications of exposure to some pesticides via breast milk and provide health-based guidance. The presence of organochlorine pesticides in breast milk has been documented in many studies around the world. Included in our review are aldrin/dieldrin, chlordane, 1,1,1-trichloro-2,2-bis(p-chlorophenyl) ethane (DDT)/1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE), endrin, hexachlorobenzene (HCB), and hexachlorocyclohexane (HCH). Toxicological and environmental data on these chemicals are compiled in toxicological profiles published by the Agency for Toxic Substances and Disease Registry (ATSDR). Based on the data, ATSDR derives chemical-specific minimal risk levels (MRLs) that assist in evaluating public health risks associated with exposure. MRLs are health-based guidance values designed to protect the most sensitive populations, including breast-fed infants. We compare MRLs and projected intakes from the breast milk for the listed pesticides, explore the possibilities of toxicological interactions, and provide health-based recommendations.

Agency for Toxic Substances and Disease Registry's 1997 priority list of hazardous substances. Latent effects--carcinogenesis, neurotoxicology, and developmental deficits in humans and animals.

In support of Superfund re-authorization legislation, the Division of Toxicology of the Agency for Toxic Substances and Disease Registry (ATSDR) prepared a chemical-specific consultation document for Congress that identified those chemicals with carcinogenic, neurological, or developmental adverse effects having a latency period longer than 6 years. The review was limited to the top 50 substances listed on ATSDR's 1997 Priority List of Hazardous Substances (Priority List). Among the top 50 chemicals, a review of the technical literature indicated that 38 (76%) were classified as "reasonably anticipated," "possibly," or "probably" capable of causing cancer in humans, based either on human and animal data. Eight chemicals (16%) had well-established cancer latency periods in humans of 6 years or more following exposure. Three substances (6%)--arsenic, creosote, and benzidine--had data indicating latency periods longer than 6 years. The technical literature review likewise confirmed the potential for neurological and developmental effects with a latency of 6 years. Twenty-seven (54%) of the top 50 substances caused acute and/or chronic neurotoxic effects; a number of these also caused neurological effects that persisted beyond 6 years (or the equivalent in animal studies) such as: behavioral problems, neurological deficiencies, reduced psychomotor development, cognitive deficiencies, and reduced IQ. Twenty-eight substances (56%) caused adverse developmental effects in offspring of exposed individuals or animals including increased fetal and infant mortality, decreased birth weights and litter sizes, and growth delays. Latency periods for related chemicals are expected to be similar due to structural and toxicological similarities.

An overview of Food and Drug Administration regulation of drugs, biologics, and devices to be used for management of periodontal diseases.

The Food and Drug Administration (FDA) has been actively involved in assuring the safety and effectiveness of medical products since 1906. The FDA was granted increased authority to regulate drugs in 1938 and devices in 1976. The regulatory requirements for marketing in the United States vary according to the type of product and the degree of risk associated with it. One route to the market is through the premarket notification [510(kappa)] process in which devices are evaluated according to their substantial equivalence to devices marketed prior to May 28, 1976. Many devices specifically intended to treat periodontal conditions have progressed through the 510(kappa) process based on their substantial equivalence to predicate devices. In some cases manufacturers have needed to provide clinical data in the form of Investigational Device Exemptions (IDE) to support an equivalence determination. Certain devices with indications for use in periodontal evaluation or therapy, specifically, those determined by FDA to be not substantially equivalent to legally marketed devices, require Premarket Approval Applications (PMA). For new drug products, clinical trials are carried out under an approved Investigational New Drug Application (IND). Application for approval for marketing is requested through a New Drug Application. Data from clinical trials conducted outside the United States may be considered by the FDA in support of the safety and effectiveness of the product. The FDA is continually developing and updating guidance documents and guidelines to assist manufacturers in gaining clearance/approval to market new products.

Regulatory issues unique to clinical trials on periodontal diagnostic methods and devices.

A wide variety of in vitro diagnostic products have been proposed for use in patients with periodontal disease. The Food and Drug Administration (FDA) review focuses on three important issues. First, the product must exhibit acceptable analytical performance (accuracy, precision, analytical sensitivity, and analytical specificity). Second, the effectiveness of the device must be clearly defined. The studies required to establish this will depend largely on the proposed intended use of the product. At a minimum, clinical or diagnostic sensitivity and specificity should be established. Finally, the product must meet the labeling requirements for in vitro devices. These requirements outlined in CFR 809.10(b) are comprehensive and cover 15 key elements including information about the principles of the analytical method; handling of instruments, reagents, and patient samples; test limitations; and test performance. Applicants developing products for any in vitro diagnostic device are encouraged to review the labeling regulations along with other divisional and office guidance material to help in defining the submission requirements. The FDA is willing to meet and work with companies prior to and during preclinical and clinical trials to assist in the development of appropriate study protocols.

The nightmare of FDA clearance/approval to market: perception or reality?

Over the last few years the Center for Device Evaluation and Research (CDRH) at the Food and Drug Administration (FDA) has received annually over 16 thousand submissions related to medical devices. Over 10,000 of these are major submissions which include applications to conduct clinical trials and applications to market medical devices for a specified indication for use. Each application is carefully considered. FDA personnel work closely with applicants to ensure that clinical trial design minimizes risk to the patients and maximizes benefit with respect to addressing the safety and effectiveness of the device being tested. Applicants are given every opportunity to provide additional information when necessary to assure that applications to market medical devices are complete. Applicants have the opportunity to meet with FDA staff prior to submitting applications in cases where the application is other than a straight forward, uncomplicated submission. In addition, FDA assists applicants through the development of guidance documents, which discuss the type of information that would be beneficial to include in a submission. The Division of Small Manufacturers Assistance at FDA is dedicated to helping interested persons understand the clearance/approval process. This paper will discuss the role of FDA in the regulation of medical devices, with an emphasis on the pathway to obtaining permission to market medical devices in the United States.

Antifungal activities of salivary histidine-rich polypeptides against Candida albicans and other oral yeast isolates.

Twenty-six oral yeast isolates from 26 donors were tested for their susceptibility to salivary histidine-rich polypeptide-4 (HRP-4) in blastospore viability assays. HRP-4 was observed to inhibit blastospore division in all of the yeast isolates, although inhibition was variable depending upon both species and strain tested. Nine species of Candida and 2 strains of Trichosporon pullulans were included in the study. No significant differences in susceptibility to HRP-4 could be seen, irrespective of where in the oral cavity the yeast isolate was obtained.

FDA regulation of dental devices: past, present, and future.

The organization of the Food and Drug Administration as related to dental devices is described. The classification according to safety and efficacy of devices is described and examples are given. The process of submitting a Premarket Notification [(510(k)] for class I and II devices, a Premarket Approval (PMA) for class III devices and an Investigational Device Exemption (IDE) are described. The clinician is told how to report problems with medical devices.

Bulimia nervosa. Its effect on salivary chemistry.

Erosion of the dental hard tissues and enlarged parotid and submandibular saliva glands are commonly associated with bulimia nervosa. In 15 patients and controls, no significant difference was detected in the concentrations of potassium, chloride, calcium, urea nitrogen or albumin. There was also no evidence of olfactory dysfunction.

Oral mucosal appearance is unchanged in healthy, different-aged persons.

Oral mucosal status in 182 different-aged, healthy, community-dwelling persons was evaluated. Ninety-four men and 88 women, ranging in age between 20 and 95 years, participated in this study. Oral mucosal status was assessed according to both subjective complaints and a semiquantitative clinical rating scale. No changes in either criterion were detected with increasing age. Oral mucosal status of the older subjects of this study was comparable to that found in a previous study with a randomly enrolled, noninstitutionalized older population in Iowa. The results of this study suggest that aging per se does not lead to changes in the appearance of oral mucosa.

A new approach to the study of tooth wear.

Human tooth wear occurs so slowly that traditionally it has needed months or years to be measurable. This study showed that microscopic changes in wear patterns on human teeth could be detected in a matter of days and could be used as indicators of rates of wear. Thus, daily or weekly changes in rates of wear can be documented for specific locations on teeth. For instance, through this new approach, rates of wear of human teeth were shown to be significantly slower than rates of wear of the teeth of laboratory monkeys raised on hard or soft diets. Similar techniques may ultimately be used to monitor subtle changes in tooth use--including those associated with growth and development and those occurring in response to various dental clinical procedures.

An assessment of salivary function in healthy premenopausal and postmenopausal females.

The elderly represent the most rapidly growing segment of the U.S. population, and the majority of this group are females. The average woman can anticipate living about a third of her life beyond menopause, and many U.S. women undergo hormonal replacement in an attempt to relieve menopausal symptoms. Little is understood about the relationship between menopause, hormonal replacement therapy, and the oral structures, although oral discomfort, xerostomia, and salivary hypofunction have been associated with postmenopausal women. The effects of menopausal status and estrogen therapy on subjective reports of oral dryness and discomfort and objective measurements of major salivary gland output were assessed in 43 healthy premenopausal and postmenopausal females. No complaints of xerostomia or burning mouth and no alterations in the quantity of saliva occurred in this population. This study suggests that among healthy women salivary gland function is not significantly influenced by menopause or hormonal replacement therapy.

Coaggregation of oral Candida isolates with bacteria from bone marrow transplant recipients.

In vitro coaggregation between Candida species isolated from immunosuppressed bone marrow transplant recipients and oral bacteria was investigated. Each Candida strain showed a different pattern of coaggregation with the 22 bacterial strains studied. Two strains of Lactobacillus amylovorus isolated from separate bone marrow transplant patients and Fusobacterium nucleatum (VPI 10197) coaggregated with all Candida strains. Ten bacterial strains showed no coaggregation with the Candida strains. A variety of inhibition patterns were observed when coaggregating strains were first incubated with various sugars or subjected to heat treatment. Positive and negative results were generally consistent with all Candida strains. On the basis of the culture characteristics of the oral rinse specimens, relationships between the colonization of bacteria and yeasts and in vitro coaggregation were suggested.

Oral sensory changes in aging.

Perception of oral sensory intensity was assessed in healthy, community-dwelling men (n = 46) and women (n = 41) between 25 and 93 years of age. Cross-modal matches of distance to perceived intensity were obtained for five types of oral stimuli (sugar water, salt water, heated or chilled water, water thickened with methylcellulose, and local pressure on the dorsal tongue). Differences among stimulus types were observed for measures of response size (mean, median, maximum, and range of response distance and rate of increase with stimulus strength), but not measures of judgment quality, repeatability (ICC), and conformity to a linear rise with stimulus strength (r2). Age had no significant effect on any of the response measures for any stimulus type except pressure. All measures of response to lingual pressure except median size declined significantly with age. We conclude that (a) the various oral stimulus types elicit perceptions that differ in intensity but were judged with similar accuracy, and that (b) aging brings a specific decline in the perception of localized lingual pressure while both size and accuracy of intensity judgments are maintained for the other oral sensitivities tested.

High levels of oral yeasts in early HIV-1 infection.

Ten human immunodeficiency virus-1 (HIV-1) infected homosexual or bisexual individuals (ages 24-45) with no history of opportunistic infection were examined, by culture, for the presence of yeasts in whole saliva and on oral mucosa. All were HIV-1 antibody-positive men, non-smokers, non-denture wearers, and taking no medication. The mean salivary level of yeast was four logs higher in the HIV-1 infected group compared to a control group of normal, unmedicated, non-smoking men (ages 20-41) who denied any risk behavior for HIV-1 infection. Identification of the yeast in these HIV-1 positive individuals established that Candida albicans was the predominant species found in whole saliva and on buccal mucosa and tongue. Distinct hyphae were observed with only one mucosal sample. No significant correlation was found between whole saliva yeast concentration and the T4/T8 lymphocyte ratios or absolute number of T4 cells. No correlation was observed between oral yeast concentration and anti-C. albicans IgA titers. The high level of oral yeast in these individuals prior to the development of opportunistic infections is consistent with the suggestion that oral defense mechanisms are compromised in individuals following HIV-1 infection.

Dysphagia in bulimia nervosa.

The findings on 13 patients with bulimia nervosa referred for evaluation of salivary glands and swallowing patterns are presented. Each patient completed a medical, oral, and social history questionnaire. A complete oral examination supported by appropriate dental radiographs and photographs was conducted. Unstimulated and stimulated parotid and submandibular saliva was collected. The presence or absence of pharyngeal and velar gag reflexes was ascertained. Real-time ultrasound scanning and barium swallow studies were used to evaluate the oral-motor functions while swallowing on 6 of the subjects. Activity of the pharynx, larynx, and esophagus was recorded during the videofluorographic studies. Saliva concentrations of amylase were determined in the referred subjects as well as 13 age-matched healthy controls. No significant difference was detected between the salivary gland flow rates and amylase concentrations of the two groups, whether stimulated or unstimulated. The pharyngeal gag reflex was absent in 9 of the 13 bulimic patients and a velar gag reflex could be elicited in only 1. All of the normal controls had both gag reflexes. All of the patients with bulimia were found to have abnormal oropharyngeal swallow patterns and an increased duration of dry swallow.

Dental aspects of anorexia and bulimia nervosa.

Anorexia nervosa and bulimia nervosa are both psychosocial pathological eating disorders. An intense preoccupation with food, weight and a distorted body image coupled with a morbid fear of becoming obese are common elements in both syndromes. Self-starvation with extreme weight loss is associated with anorexia nervosa. Bulimia nervosa is characterized by unrestrained eating sprees followed by purging, fasting or vomiting. Approximately 50% of anorexia nervosa patients also practice bulimia. The impact of eating disorders on the oral soft and hard tissues depends upon the diet as well as the duration and frequency of binge-purge behavior. Erosion of the teeth due to frequent regurgitation of highly acidic stomach contents is a common finding. Dental caries development is less predictable and appears to be diet- and oral hygiene-dependent. Painless enlargement of the parotid salivary glands is a common sequela of chronic vomiting but the pathophysiological cause has not been firmly established. The dehydration of the oral soft tissues due to salivary gland impairment in addition to dietary deficiencies and poor oral hygiene can adversely impact the health of the periodontal tissues and oral mucosa. Initial dental care is focused on discouraging behavior that is destructive to the oral tissues. Improved oral hygiene, the use of gastric acid-neutralizing antacid rinses and the daily application of topical fluorides can be useful in reducing enamel erosion. Extensive restorative oral rehabilitation should be postponed until the underlying psychiatric components of the disorder are stabilized.

Evaluation of submandibular salivary flow rate in different age groups.

The production of unstimulated and citrate-stimulated submandibular saliva was examined in 90 male and female adults, aged 26-93 years. None was taking prescription medications for treatment of systemic disease. There was no diminution in submandibular gland fluid output, at rest or during stimulation, with increasing age. Similar findings, previously reported for the parotid glands, were also confirmed. These results demonstrate that major gland fluid secretion capacity is maintained in healthy older individuals.

Oral defense mechanisms are impaired early in HIV-1 infected patients.

We have examined the hypothesis that individuals infected with human immune deficiency virus type 1 (HIV-1) experience significant, specific alterations in mechanisms protecting the oral cavity prior to the appearance of AIDS-related systemic opportunistic infections. In a study of 13 early-stage, stable anti-HIV antibody positive patients, parotid salivary function was found to be generally intact. In contrast, several indicators of submandibular gland dysfunction were detected. In particular, stimulated fluid output was decreased and salivary lysozyme levels were increased relative to controls by 50-60% for both resting (p less than 0.05) and stimulated (p less than 0.001) conditions. Also, the frequency of albumin detection in submandibular saliva samples was approximately 65% in HIV-1 infected patients vs. 0% in controls (p less than 0.05). In addition, cytologic evaluation of oral mucosa revealed a fivefold increase in the prevalence of candidal hyphae in HIV-1 infected patients compared to controls (41% vs. 8%, p less than 0.05). We conclude that normal oral defense mechanisms show signs of compromise in HIV-1 infected individuals. We suggest that (a) effects of HIV-1 infection are seen early in the oral cavity, (b) impairment of oral defense mechanisms may facilitate entry of microorganisms with an attendant increased risk of morbidity and mortality, and (c) intensive oral surveillance and prophylactic care should be part of the routine management afforded to AIDS patients soon after HIV-1 infection is recognized.

Use of lytic bacteriophage for Actinomyces viscosus T14V as a probe for cell surface components mediating intergeneric coaggregation.

A lytic bacteriophage for Actinomyces viscosus T14V (the reference strain for actinomyces coaggregation group A) was isolated from raw sewage. This phage, designated BF307, also lysed the T14V-derived nonfimbriated mutant PK455-2 as well as A. viscosus MG-1 and T14AV but not the other serotype 2 or serotype 1 strains of this species that were tested or any of nine Actinomyces naeslundii isolates. Phages BF307 belonged to Bradley morphological group C and was similar in appearance to the A. viscosus MG-1 phages Av-1 and Av-3, which do not productively infect A. viscosus T14V. A. viscosus MG-1 mutants selected for resistance to phage BF307, Av-3, or CT7 (a human dental plaque isolate with the same host range as BF307) were coresistant to the other two phages but sensitive to Av-1. These results indicate that the receptors on A. viscosus MG-1 for phages BF307, Av-3, and CT7 are identical or share a common precursor and that the receptor for phage Av-1 is distinct. Comparison of the genomes of BF307, Av-3, and CT7 revealed that their DNAs were similar in size but distinguishable by restriction analysis. Two altered coaggregation phenotypes were identified among the phage BF307-resistant mutants of strains MG-1, T14V, T14AV, and PK455-2. Class I mutants had lost the ability to interact with coaggregation group 1 streptococci, and class II mutants did not coaggregate with either group 1 or group 2 streptococci. These results are consistent with the proposal that the phage BF307 receptor on these A. viscosus strains is related to one of the structures that mediates coaggregation with oral streptococci. A model to delineate the various coaggregation mediators on the surface of actinomyces coaggregation group A cells is presented, and the use of these phages to probe surface components of human oral actinomyces strains is discussed.