Definition of T cell idiotypes using anti-idiotypic antisera produced by immunization with T cell clones.

Alloreactive T cell clones with distinct specificities were used to raise anti-idiotypic antisera via an F1 anti-(parent anti-F1) protocol. Antisera were raised that could stimulate the proliferation of the appropriate T cell clone, but not other clones. The active fraction of the antisera for T cell proliferation was immunoglobulin. In addition to proliferation, an anti-idiotypic antiserum could induce the appropriate T cell clone to secrete substantial amounts of interleukin 2 (IL-2). Production of IL-2 appeared independent of the involvement of accessory cells. These accessory cells may be unnecessary for IL-2 production in our assay, or their effect may be produced by anti-idiotype. Thus, anti-idiotype may provide two or more specific T cell signals.

Mutagenic and carcinogenic risks associated with halogenated olefins.

Recent experimental evidence indicates that structural analogs of vinyl chloride namely, vinylidene chloride and trichloroethylene, are mutagenic. Carcinogenic response also has been observed in experimental animals following exposure to vinylidene chloride, trichloroethylene, and perchloroethylene. More recent observations demonstrate low-level vinyl chloride-induced mammary carcinoma. An additional chlorinated olefin, chloroprene, has demonstrated a mutagenic response in several test systems. Likewise, several studies have indicated significant excesses of chromosomal aberrations as well as adverse effects on reproductive function following male exposure to chloroprene. Although reports have indicated an increased incidence of lung and skin cancer among workers occupationally exposed to chloroprene, adequately designed studies have not been carried out which would allow the development of valid inferences regarding its carcinogenicity. The question facing the scientific community and society is whether observations in subhuman species are adequate to institute prudent public health practice by controlling these agents as carcinogens or mutagens or whether, once again, epidemiologic enumeration of the toll will be required.

Observations of the site-specific carcinogenicity of vinyl chloride to humans.

A review of epidemiologic studies of workers exposed to vinyl chloride (VC) was conducted. Some of these studies comprised small cohorts and thus were insensitive in the evaluation of carcinogenic response for sites that do not demonstrate a high relative risk. Other larger studies used methodology and design that precluded an interpretation of the results. Such limitations were acknowledged by some authors. Use of restrictive disease rubrics also lead to the submerging of sites that would have demonstrated significant excesses. For example, some investigators analyzed data for liver cancer deaths with the board category of digestive system cancer deaths, while others combined data for CNS cancer deaths with the broad category of "other and unspecified cancer," and most studies analyzed information for lymphatic and hematopoietic system cancer deaths with all data combined. Only four of eight studies reviewed could demonstrate a significant excess of liver cancer among VC-exposed workers--a site confirmed in humans by 1974. In contrast, five of eight studies appear to demonstrate a significant excess of CNS cancer mortality. Workers exposed to VC also demonstrate a significant excess of mortality for lung cancer, while the data for lymphatic and hematopoietic system cancer are suggestive. Interpretation of cancer of the latter systems may have been clarified if investigators had not analyzed their data by broad disease classifications.

State of the science on the carcinogenicity of gasoline with particular reference to cohort mortality study results.

As a result of the content of benzene in various streams of refinery products, including gasoline, it is not surprising that over the years studies and case reports have linked gasoline exposure to lymphopoietic cancers (LPC), particularly leukemia and multiple myeloma (MM). Of three recently conducted studies of gasoline-exposed workers, one shows strong associations with leukemia and MM, a second suggests some association with leukemia and did not analyze data for MM, and the third study is not possible to evaluate because of a major problem with study design. Other diseases of particular interest in relation to gasoline exposure are kidney cancer, malignant melanoma, and heart disease. One study suggests an association with kidney cancer, but the second study did not. There appears to be no association between employment in refineries or gasoline exposure and heart disease. However, evaluation of risk of kidney cancer and heart disease is somewhat difficult because investigators did not control for cigarette smoking, even though it is related to these diseases. This is of particular concern when studying gasoline-exposed workers, who because of the explosive nature of gasoline probably smoke less than the general population used for comparison of mortality. Some studies of refinery workers and gasoline-exposed workers in particular show an excess risk of death from malignant melanoma. Whether this latter association is the result of benzene/gasoline exposure, sunlight exposure, or a combination of the two cannot be determined with the data currently available.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of rodent carcinogenicity test results for determining potential cancer risk to humans.

A high proportion of "human" and "probable human" carcinogens as categorized by the International Agency for Research on Cancer have been identified through observations in workers. The excess cancer risk has often been quite high. Most substances known to cause cancer in humans are now known to cause cancer in animals. In the past two decades, an increasing number of substances first shown to cause cancer in animals are now known to cause or are highly suspected of causing cancer in humans (and quite often in workers). The observations necessitate the use of rodent cancer test results for identifying and regulating potential environmental carcinogens. The role of cell proliferation (CP) in the carcinogenic response is important from a regulatory view in terms of both qualitative and quantitative evidence. If CP influences the carcinogenic response, the use of such data to modify dose response in the low-dose range is another factor that needs to be considered. Presentations at this symposium, however, indicate that CP data at the present time should not be incorporated into cancer risk assessments. More simple concepts that affect quantitative dose response and that may result in an artificially low estimated risk but could be adjusted for in the bioassay protocol have usually been ignored. A balanced approach would be to incorporate all known factors that influence quantitative estimates of cancer risk when conducting animal cancer bioassays and extrapolating those results to humans.

Review of epidemiologic study results of vinyl chloride-related compounds.

Epidemiologic study results addressing the carcinogenicity of six compounds related to vinyl chloride (vinylidene chloride, trichloroethylene, perchloroethylene, carbon tetrachloride, ethylene dibromide and epichlorohydrin) are reviewed. The study results suggest an increased carcinogenic risk among workers exposed to epichlorohydrin and to dry cleaning and degreasing solvents. Although several studies report no significant excess of cancer mortality, an evaluation of the design of these investigations demonstrates that these negative cohort studies consisted of populations of insufficient sample size and latency to permit any meaningful conclusions regarding carcinogenic risk. Therefore, experimental studies must be relied upon to determine whether several of these substances pose a potential carcinogenic risk to humans. Available evidence indicates that all of these substances have demonstrated a carcinogenic response in experimental animals and most are mutagenic in experimental test systems.

Benzene: epidemiologic observations of leukemia by cell type and adverse health effects associated with low-level exposure.

Benzene has been known to be a bone marrow poison for almost a century. However, it was not until the last decade that benzene's carcinogenic potential was demonstrated by epidemiologic studies. The proposed regulation by the Occupational Safety and Health Administration (OSHA) to lower exposure levels of benzene in the workplace, and the court challenges that followed, have made the evidence of benzene toxicity a frequent topic of discussion and analysis. Epidemiologic evidence of leukemia risk associated with benzene exposure is summarized, including a discussion of certain contentions raised during the OSHA hearing. Special attention is given to information on specific cell types of leukemia associated with benzene and to qualitative and quantitative assessments of health risks associated with low-level benzene exposure.

An epidemiologic study of deciduous molar relations in preschool children.

This study indicated that distoclusion decreased significantly with age and was more prevalent in siblings of children with Class II molar relation as compared with the prevalence for the total population. Children of middle socioeconomic status (SES) and girls with Class I molar relation had prevalences of posterior crossbite significantly greater than lower SES children and boys, respectively. Finger habits were highly associated with posterior crossbite (P less than 0.001).

Dental caries experience in the deciduous dentition of rural Guatemalan children ages 6 months to 7 years.

A study of 528 Guatemalan children indicated that caries prevalence in the deciduous dentition was twice as great as but in the permanent dentition was similar to that for US white children. This is a repeated observation for children of some preindustrial societies. Caries experience was significantly greater in boys. Until 4 years of age, caries attack was greater in the anterior segment of the oral cavity; linear enamel hypoplasia was a predisposing factor.

Enamel hypoplasia in relation to caries in Guatemalan children.

Guatemalan children with anterior linear enamel hypoplasia (LEH) had a significantly greater caries experience in posterior dentition than their peers who did not have anterior LEH. The findings suggest that the synergistic mechanism of undernutrition and infection, which may underlie the occurrence of anterior LEH, may also predispose clinically normal appearing deciduous molars to an excessive caries attack equal to that observed in the grossly hypoplastic anterior teeth. The nutritional implications merit further investigation.

Carcinogenic, mutagenic and teratogenic risks associated with vinyl chloride.

The data presented demonstrate clearly that vinyl chloride (VC) is related to a significant excess of mortality from cancer of the liver, lung and brain among workers occupationally exposed to VC. The risk of dying from cancer of the lymphatic and hematopoietic system also appears to increase with an increase in latency. These cancer sites could have been predicted by the animal bioassay conducted by Maltoni. With regard to the liver, even the histophthologic type of cancer (angiosarcoma) was observed first in experimental animals. A study of cancer mortality among populations residing proximate to VC polymerization facilities also demonstrated an increased risk of dying from CNS and lymphatic cancer. These latter findings raise cause for concern about out-plant emmissions of VC, but without further study these cancers obviously cannot be interpreted as being related to out-plant exposure to VC. Various test systems now have elicited a positive mutagenic response to VC. Thus, our observations of a significant excess of fetal mortality among the wives of males, who were occupationally exposed to VC, raise public health concern that VC may be mutagenic in humans. With regard to the teratogenicity of VC, observations of a significant excess of children born with birth defects were reported among populations residing proximate to VC polymerization facilities. Additional epidemiologic study is needed to determine whether a repeated pattern of excessive numbers of children born with birth defects can be observed in other communities with VC polymerization facilities.

Severe cervical chyle fistula after radical neck dissection.

The case of a chylous cervical fistula detected immediately after radical neck dissection is presented. The flow and metabolic derangements secondary to depletion of fluid, electrolytes, and protein required the ligation of the thoracic duct at the thoracic cavity. The various possible treatments of chylous fistula are reviewed.

Development of the Occupational Safety and Health Administration's proposed standard to protect workers from contracting bloodborne diseases in the workplace.

The Occupational Safety and Health Administration (OSHA) is in the process of developing a health standard to protect workers by reducing occupational exposure to hepatitis B virus, human immunodeficiency virus, and other bloodborne pathogens. This article reviews the history of the standard, the steps involved in OSHA standard development, and--most specifically--how the dental professional can participate in this process.

PCAF ubiquitin ligase activity inhibits Hedgehog/Gli1 signaling in p53-dependent response to genotoxic stress.

The Hedgehog (Hh) signaling regulates tissue development, and its aberrant activation is a leading cause of malignancies, including medulloblastoma (Mb). Hh-dependent tumorigenesis often occurs in synergy with other mechanisms, such as loss of p53, the master regulator of the DNA damage response. To date, little is known about mechanisms connecting DNA-damaging events to morphogen-dependent processes. Here, we show that genotoxic stress triggers a cascade of signals, culminating with inhibition of the activity of Gli1, the final transcriptional effector of Hh signaling. This inhibition is dependent on the p53-mediated elevation of the acetyltransferase p300/CBP-associated factor (PCAF). Notably, we identify PCAF as a novel E3 ubiquitin ligase of Gli1. Indeed PCAF, but not a mutant with a deletion of its ubiquitination domain, represses Hh signaling in response to DNA damage by promoting Gli1 ubiquitination and its proteasome-dependent degradation. Restoring Gli1 levels rescues the growth arrest and apoptosis effect triggered by genotoxic drugs. Consistently, DNA-damaging agents fail to inhibit Gli1 activity in the absence of either p53 or PCAF. Finally, Mb samples from p53-null mice display low levels of PCAF and upregulation of Gli1 in vivo, suggesting PCAF as potential therapeutic target in Hh-dependent tumors. Together, our data define a mechanism of inactivation of a morphogenic signaling in response to genotoxic stress and unveil a p53/PCAF/Gli1 circuitry centered on PCAF that limits Gli1-enhanced mitogenic and prosurvival response.

Numb activates the E3 ligase Itch to control Gli1 function through a novel degradation signal.

Hedgehog pathway regulates tissue patterning and cell proliferation. Gli1 transcription factor is the major effector of Hedgehog signaling and its deregulation is often associated to medulloblastoma formation. Proteolytic processes represent a critical mechanism by which this pathway is turned off. Here, we characterize the regulation of an ubiquitin-mediated mechanism of Gli1 degradation, promoted by the coordinated action of the E3 ligase Itch and the adaptor protein Numb. We show that Numb activates the catalytic activity of Itch, releasing it from an inhibitory intramolecular interaction between its homologous to E6-AP C-terminus and WW domains. The consequent activation of Itch, together with the recruitment of Gli1 through direct binding with Numb, allows Gli1 to enter into the complex, resulting in Gli1 ubiquitination and degradation. This process is mediated by a novel Itch-dependent degron, composed of a combination of two PPXYs and a phospho-serine/proline motifs, localized in Gli1 C-terminal region, indicating the role of two different WW docking sites in Gli1 ubiquitination. Remarkably, Gli1 protein mutated in these modules is no longer regulated by Itch and Numb, and determines enhanced Gli1-dependent medulloblastoma growth, migration and invasion abilities, as well as in vitro transforming activity. Our data reveal a novel mechanism of regulation of Gli1 stability and function, which influences Hedgehog/Gli1 oncogenic potential.