A preliminary operational classification system for nonmutagenic modes of action for carcinogenesis.

This article proposes a system of categories for nonmutagenic modes of action for carcinogenesis. The classification is of modes of action rather than individual carcinogens, because the same compound can affect carcinogenesis in more than one way. Basically, we categorize modes of action as: (1) co-initiation (facilitating the original mutagenic changes in stem and progenitor cells that start the cancer process) (e.g. induction of activating enzymes for other carcinogens); (2) promotion (enhancing the relative growth vs differentiation/death of initiated clones (e.g. inhibition of growth-suppressing cell-cell communication); (3) progression (enhancing the growth, malignancy, or spread of already developed tumors) (e.g. suppression of immune surveillance, hormonally mediated growth stimulation for tumors with appropriate receptors by estrogens); and (4) multiphase (e.g., "epigenetic" silencing of tumor suppressor genes). A priori, agents that act at relatively early stages in the process are expected to manifest greater relative susceptibility in early life, whereas agents that act via later stage modes will tend to show greater susceptibility for exposures later in life.

The inter-observer reproducibility of Shafer's sign.

Pigment cells in the anterior vitreous (Shafer's sign) are known to be associated with retinal breaks. We sought to identify the reproducibility of Shafer's sign between different grades of ophthalmic staff. In all 47 patients were examined by a consultant vitreo-retinal surgeon, a senior house officer (SHO) and optician for Shafer's sign. Cohen's kappa for consultant vs SHO assessment of Shafer's sign was 0.55 while for consultant vs optician assessment, kappa was 0.28. Retinal tears were present in 63.8% of our series. Consultant assessment of Shafer's sign with fundoscopy findings, we found specificity to be 93.5% while sensitivity was 93.8%. Kappa for consultant assessment of Shafer's sign vs break presence was 0.86.Consultant and SHO assessment of Shafer's sign is of moderate agreement while optician assessment is fair. These results suggest a relationship between training and the assessment of Shafer's sign. We feel this study suggests caution in undue reliance on Shafer's sign particularly for inexperienced members of staff.

Ocular findings in low birthweight and premature babies in the first year: do we need to screen?

PURPOSE: There is no standardized approach for the ophthalmic care follow-up of children screened for retinopathy of prematurity (ROP). The authors report the ocular findings at 12 months in preterm and low birthweight babies screened for ROP over a 5-year period (1998-2003). METHODS: The case notes of 211 babies were retrospectively reviewed for birth details, maternal details, presence of ROP, and findings at follow-up screening which included visual acuity, refraction at 12 months, presence of squint, and any other ocular problems. RESULTS: At 1 year follow-up, 16.6% of ROP positive children failed a screening visit because of squint (6.66%), refractive error (6.66%), and optic nerve abnormalities (3.33%). At 1 year follow-up, 10% of ROP negative children had failed a screening visit because of squint (3.75 %), refractive error (3.75%), and other pathology (2.5%). CONCLUSIONS: The authors recommend screening all babies with ROP at 12 months to identify amblyogenic factors such as squint and refractive error. Parents of infants who do not develop ROP should be advised of the increased risk of visual problems in their children and to have their child examined in the preschool period.

Diagnostic effectiveness of noncontact slitlamp examination in the identification of retinal tears.

PURPOSE: To compare the diagnostic accuracy of noncontact slitlamp examination with indirect ophthalmoscopy and scleral depression, in the identification of retinal tears. METHODS: A prospective study was performed using 17 patients who were referred with retinal tears. All were initially examined at the slitlamp with a hand-held Volk (noncontact) lens. The same observer then carried out indirect ophthalmoscopy with scleral indentation. RESULTS: In 17 eyes a total of 18 acute retinal u-tears were found. A total of 16 tears were picked up at the initial examination at the slitlamp (89%), while two were missed (11%). CONCLUSIONS: Indirect ophthalmoscopy with scleral depression is the 'gold standard' for the identification of peripheral retinal tears. This small study has shown that although the majority of these can be picked up by the use of a noncontact lens at the slitlamp, 11% were missed using this technique.

Human interindividual variability in susceptibility to airborne particles.

Part of the explanation for the persistent epidemiological findings of associations between mortality and morbidity with relatively modest ambient exposures to airborne particles may be that some people are much more susceptible to particle-induced responses than others. This study assembled a database of quantitative observations of interindividual variability in pharmacokinetic and pharmacodynamic parameters likely to affect particle response. The pharmacodynamic responses studied included data drawn from epidemiologic studies of doses of methacholine, flour dust, and other agents that induce acute changes in lung function. In general, the amount of interindividual variability in several of these pharmacodynamic response parameters was greater than the variability in pharmacokinetic (breathing rate, deposition, and clearance) parameters. Quantitatively the results indicated that human interindividual variability of breathing rates and major pharmacokinetic parameters-total deposition and tracheobronchial clearance-were in the region of Log(GSD) = 0.1 to 0.2 (corresponding to geometric standard deviations of 10(.1)-10(.2) or 1.26-1.58). Deposition to the deep lung (alveolar region) appeared to be somewhat more variable: Log(GSD) of about 0.3 (GSD of about 2). Among pharmacodynamic parameters, changes in FEV1 in response to ozone and metabisulfite (an agent that is said to act primarily on neural receptors in the lung) were in the region of Log(GSD) of 0.2 to 0.4. However, similar responses to methacholine, an agent that acts on smooth muscle, seemed to have still more variability (0.4 to somewhat over 1.0, depending on the type of population studied). Similarly high values were suggested for particulate allergens. Central estimates of this kind of variability, and the close correspondence of the data to lognormal distributions, indicate that 99.9th percentile individuals are likely to respond at doses that are 150 to 450-fold less than would be needed in median individuals. It seems plausible that acute responses with this amount of variability could form part of the mechanistic basis for epidemiological observations of enhanced mortality in relation to ambient exposures to fine particles.

Performance evaluation of the microPET P4: a PET system dedicated to animal imaging.

The microPET Primate 4-ring system (P4) is an animal PET tomograph with a 7.8 cm axial extent, a 19 cm diameter transaxial field of view (FOV) and a 22 cm animal port. The system is composed of 168 detector modules, each with an 8 x 8 array of 2.2 x 2.2 x 10 mm3 lutetium oxyorthosilicate crystals, arranged as 32 crystal rings 26 cm in diameter. The detector crystals are coupled to a Hamamatsu R5900-C8 PS-PMT via a 10 cm long optical fibre bundle. The detectors have a timing resolution of 3.2 ns, an average energy resolution of 26%, and an average intrinsic spatial resolution of 1.75 mm. The system operates in 3D mode without inter-plane septa, acquiring data in list mode. The reconstructed image spatial resolution ranges from 1.8 mm at the centre to 3 mm at 4 cm radial offset. The tomograph has a peak system sensitivity of 2.25% at the centre of the FOV with a 250-750 keV energy window. The noise equivalent count rate peaks at 100-290 kcps for representative object sizes. Images from two phantoms and three different types of laboratory animal demonstrate the advantage of the P4 system over the original prototype microPET. including its threefold improvement in sensitivity and a large axial FOV sufficient to image an entire mouse in a single bed position.

Vitrectomy for retinal detachments with both peripheral retinal breaks and macular holes. An assessment of outcome and the status of the macular hole.

PURPOSE: To establish the effectiveness of vitrectomy and gas tamponade for treating retinal detachments due to peripheral retinal breaks with an associated macular hole and to discover the status of the macular hole at long-term follow-up. METHODS: Twenty-three consecutive patients with combined peripheral break and macular hole retinal detachments were treated by pars plana vitrectomy. The main outcome measures were reattachment of the retina and status of the macular hole. RESULTS: Seventy-eight percent of the operations were successful in reattaching the retina initially, improving to 87% after two patients had another operation. Three patients declined further surgery. Long-term follow-up of macular hole status was possible in 16 cases. Closure rate was 31%. CONCLUSION: Pars plana vitrectomy with gas tamponade is an effective method of treating this form of retinal detachment. Some macular holes close after this surgery.

The assessment of radiation exposures in Native American communities from nuclear weapons testing in Nevada.

Native Americans residing in a broad region downwind from the Nevada Test Site during the 1950s and 1960s received significant radiation exposures from nuclear weapons testing. Because of differences in diet, activities, and housing, their radiation exposures are only very imperfectly represented in the Department of Energy dose reconstructions. There are important missing pathways, including exposures to radioactive iodine from eating small game. The dose reconstruction model assumptions about cattle feeding practices across a year are unlikely to apply to the native communities as are other model assumptions about diet. Thus exposures from drinking milk and eating vegetables have not yet been properly estimated for these communities. Through consultations with members of the affected communities, these deficiencies could be corrected and the dose reconstruction extended to Native Americans. An illustration of the feasibility of extending the dose reconstruction is provided by a sample calculation to estimate radiation exposures to the thyroid from eating radio-iodine-contaminated rabbit thyroids after the Sedan test. The illustration is continued with a discussion of how the calculation results may be used to make estimates for other tests and other locations.

The role of preoperative subconjunctival mydricaine and topical diclofenac sodium 0.1% in maintaining mydriasis during vitrectomy.

PURPOSE: To establish the role of preoperative subconjunctival mydricaine and diclofenac 0.1% in maintaining mydriasis during vitrectomy. METHODS: Fifty-seven patients were entered into the study. All were given cyclopentolate 1% and phenylephrine 2.5% preoperatively. Each patient was randomly allocated to one of three groups. In Group 1, patients received mydricaine by subconjunctival injection and diclofenac 0.1% topically preoperatively. In Group 2, patients received only subconjunctival mydricaine. Group 3 patients received only topical diclofenac preoperatively. Pupil diameter was measured with calipers before and at the end of the operation. RESULTS: There was no statistically significant difference in the change in pupil size between Groups 2 and 3. In all patients in Group 1 (who received both subconjunctival mydricaine and diclofenac preoperatively), pupil size was either maintained or increased after vitrectomy. This result was statistically significant when compared with the other groups (for Group 1 versus Group 2, P<0.005; for Group 1 versus Group 3, P<4.7x10(-06)). CONCLUSION: Topical diclofenac is useful for maintaining pupil size during vitrectomy only when used in conjunction with subconjunctival mydricaine, especially in patients in whom prolonged surgery is anticipated.

Participatory research strategies in nuclear risk management for native communities.

The Nuclear Risk Management for Native Communities (NRMNC) project is a collaborative academic, community-based, tribal project, which conducts the three essential elements of participatory research: research, education, and community action, named here as "community-based hazards management." This article describes the goals and outcomes of this effort in assisting Native American communities in Nevada, Utah, and Southern California affected by nuclear fallout from U.S. weapons testing in the 1950s and 1960s. The NRMNC project sought to create new models for dealing with health research and risk communication needs in an environmental justice setting. The following results of this four-year project are discussed: (1) building a community-based environmental health infrastructure, (2) building community capacities through workshops and educational materials, (3) conducting both technical and community research, and (4) facilitating community-based hazards management planning. We describe such positive outcomes as the improvements in the scientific database through participatory research activities, the development of equitable relationships between scientists and community members, and the creation of a sustaining program intervention for long-term community needs. The project's outcomes are presented as an expansion to limited scientific risk management outcomes in the environmental health field that often are solely quantitative and lack relevance to community concerns about environmental health impacts from contamination.

Human interindividual variability in parameters related to health risks.

This paper reviews existing data on the variability in parameters relevant for health risk analyses. We cover both exposure-related parameters and parameters related to individual susceptibility to toxicity. The toxicity/susceptibility data base under construction is part of a longer term research effort to lay the groundwork for quantitative distributional analyses of non-cancer toxic risks. These data are broken down into a variety of parameter types that encompass different portions of the pathway from external exposure to the production of biological responses. The discrete steps in this pathway, as we now conceive them, are: Contact Rate (Breathing rates per body weight; fish consumption per body weight) Uptake or Absorption as a Fraction of Intake or Contact Rate General Systemic Availability Net of First Pass Elimination and Dilution via Distribution Volume (e.g., initial blood concentration per mg/kg of uptake) Systemic Elimination (half life or clearance) Active Site Concentration per Systemic Blood or Plasma Concentration Physiological Parameter Change per Active Site Concentration (expressed as the dose required to make a given percentage change in different people, or the dose required to achieve some proportion of an individual's maximum response to the drug or toxicant) Functional Reserve Capacity-Change in Baseline Physiological Parameter Needed to Produce a Biological Response or Pass a Criterion of Abnormal Function Comparison of the amounts of variability observed for the different parameter types suggests that appreciable variability is associated with the final step in the process-differences among people in "functional reserve capacity." This has the implication that relevant information for estimating effective toxic susceptibility distributions may be gleaned by direct studies of the population distributions of key physiological parameters in people that are not exposed to the environmental and occupational toxicants that are thought to perturb those parameters. This is illustrated with some recent observations of the population distributions of Low Density Lipoprotein Cholesterol from the second and third National Health and Nutrition Examination Surveys.

Distributions of individual susceptibility among humans for toxic effects. How much protection does the traditional tenfold factor provide for what fraction of which kinds of chemicals and effects?

A significant data base has been assembled on human variability in parameters representing a series of steps in the pathway from external exposure to the production of biological responses: contact rate (e.g., breathing rates/body weight, fish consumption/body weight); uptake or absorption (mg/kg)/intake or contact rate; general systemic availability net of first pass elimination and dilution; systemic elimination or half-life; active site availability/general systemic availability; physiological parameter change/active site availability; functional reserve capacity--change in baseline physiological parameter needed to pass a criterion of abnormal function or exhibit a response. This paper discusses the current results of analyzing these data to derive estimates for distributions of human susceptibility to different routes of exposure and types of adverse effects. The degree of protection is tentatively evaluated by projecting the incidences of effects that would be expected for a tenfold lowering of exposure from a 5% incidence level if the population distribution of susceptibility were truly log-normal out to the extreme tails, and if the populations, chemicals, and responses that gave rise to the underlying data were representative of the cases to which traditional uncertainty factor is applied. The results indicate that, acting by itself, a tenfold reduction in dose from a 5% effect level is associated with effect incidences ranging from slightly less than one in ten thousand, for a median chemical/response, to a few per thousand, for chemicals and responses that have greater human interindividual variability than 19 out of 20 typical chemicals/responses. In practice, for many of the cases where the traditional tenfold factor is applied, additional protection is provided by other uncertainty factors. Nevertheless, the results generate some reason for concern that current application of traditional safety or uncertainty factor approaches may allow appreciable incidences of responses in some cases.

Are we screening too many babies for retinopathy of prematurity?

A retrospective, hospital-records-based study of neonates screened for retinopathy of prematurity (ROP) was undertaken to determine whether the inclusion criteria for screening could have been safely altered to reduce the numbers of babies screened whilst not missing any stage III disease. Babies from six neonatal intensive care units in Birmingham were screened by a single examiner. Between November 1989 and November 1995, 1611 babies were examined and 1429 of these fell within the inclusion criteria of current guidelines for ROP screening produced by the Royal College of Ophthalmologists and the British Association of Perinatal Medicine--any baby < or = 1500 g birthweight or < or = 31 weeks gestational age. Thirty-nine (39) babies developed stage III ROP of which 31 (2.2%) were from Birmingham. In addition 8 babies with stage III ROP were referred from elsewhere. All 39 babies with stage III ROP had a birthweight < or = 1250 g or a gestational age of < or = 29 weeks, but 2 fell outside one criterion, indicating the need for both to be used. Had these inclusion criteria been utilised during this period, then 30% fewer babies would have been examined (432 of 1429). The importance of using both birthweight and gestational age as inclusion criteria is discussed, and the dangers of altering the indications for national screening on the basis of one study population is emphasised.

Comparison of contact site cancer potency across dose routes: case study with epichlorohydrin.

Risk assessment for airborne carcinogens is often limited by a lack of inhalation bioassay data. While extrapolation from oral-based cancer potency factors may be possible for some agents, this is not considered feasible for contact site carcinogens. The change in contact sites (oral: g.i. tract; inhalation: respiratory tract) when switching dose routes leads to possible differences in tissue sensitivity as well as chemical delivery. This research evaluates the feasibility to extrapolate across dose routes for a contact site carcinogen through a case study with epichlorohydrin (EPI). EPI cancer potency at contact sites is compared across three bioassays involving different dose routes (gavage, drinking water, inhalation) through the use of dosimetry models to adjust for EPI delivery to contact sites. Results indicate a large disparity (two orders of magnitude) in potency across the three routes of administration when expressed as the externally applied dose. However, when expressed as peak delivered dose, inhalation and oral potency estimates are similar and overall, the three potency estimates are within a factor of seven. The results suggest that contact site response to EPI is more dependent upon the rate than the route of delivery, with peak concentration the best way to extrapolate across dose routes. These results cannot be projected to other carcinogens without further study.

Radiotherapy treatment of age-related subfoveal neovascular membranes in patients with good vision.

This prospective study investigated whether low-dose ionising radiotherapy preserved vision and caused membrane regression in patients with age-related subfoveal neovascular membranes (SFNVMs) or vascularised pigment epithelial detachments (PEDs) and relatively good initial visual acuities. Twenty-five patients with initial Snellen acuities of 6/24 or better were treated with low-dose external beam radiotherapy. Of the patients with SFNVMs, visual acuities were maintained or improved in 58% at 6 months and 53% at 1 year. Neovascular membrane size was assessed by image analysis and showed some regression in 47% and 41% at 6 and 12 months respectively. These results suggest that patients with SFNVMs and good vision may benefit from radiotherapy, faring better than previous reports of the natural history of this condition. Conversely, patients with vascularised PEDs did not appear to benefit from radiotherapy. Only 17% maintained their vision at 1 year and 33% suffered retinal pigment epithelial tears. The results from patients with SFNVMs and good initial vision, excluding those with vascularised PEDs, are encouraging however, any benefit from this treatment needs to be proven by controlled trials with long follow-up.