Ribozyme-mediated reduction of wild-type and mutant cartilage oligomeric matrix protein (COMP) mRNA and protein.

Dominant-negative mutations in the homopentameric extracellular matrix glycoprotein cartilage oligomeric matrix protein (COMP) result in inappropriate intracellular retention of misfolded COMP in the rough endoplasmic reticulum of chondrocytes, causing chondrocyte cell death, which leads to two skeletal dysplasias: pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (EDM1). COMP null mice show no adverse effects on normal bone development and growth, suggesting a possible therapy involving removal of COMP mRNA. The goal of this study was to assess the ability of a hammerhead ribozyme (Ribo56, designed against the D469del mutation) to reduce COMP mRNA expression. In COS7 cells transfected with plasmids that overexpress wild-type or mutant COMP mRNA and Ribo56, the ribozyme reduced overexpressed normal COMP mRNA by 46% and mutant COMP mRNA by 56% in a dose-dependent manner. Surprisingly, the use of recombinant adenoviruses to deliver wild-type or mutant COMP mRNA and Ribo56 simultaneously into COS7 cells proved problematic for the activity of the ribozyme to reduce COMP expression. However, in normal human costochondral cells (hCCCs) infected only with adenoviruses expressing Ribo56, expression of endogenous wild-type COMP mRNA was reduced in a dose-dependent manner by 50%. In chondrocytes that contain heterozygous COMP mutations (D469del, G427E and D511Y) that cause PSACH, Ribo56 was more effective at reducing COMP mRNA (up to 70%). These results indicate that Ribo56 is effective at reducing mutant and wild-type COMP levels in cells and suggests a possible mode of therapy to reduce the mutant protein load.

Reduction of setup uncertainties and tumor motion in the radiation therapy of lung tumors

Because the goal of radiation therapy is to deliver a lethal dose to the tumor, accurate information on the location of the tumor needs to be known. Margins are placed around the tumor to account for variations in the daily position of the tumor. If tumor motion and patient setup uncertainties can be reduced, margins that account for such uncertainties in tumor location in can be reduced allowing dose escalation, which in turn could potentially improve survival rates. ^ In the first part of this study, we monitor the location of fiducials implanted in the periphery of lung tumors to determine the extent of non-gated and gated fiducial motion, and to quantify patient setup uncertainties. In the second part we determine where the tumor is when different methods of image-guided patient setup and respiratory gating are employed. In the final part we develop, validate, and implement a technique in which patient setup uncertainties are reduced by aligning patients based upon fiducial locations in projection images. ^ Results from the first part indicate that respiratory gating reduces fiducial motion relative to motion during normal respiration and setup uncertainties when the patients were aligned each day using externally placed skin marks are large. The results from the second part indicate that current margins that account for setup uncertainty and tumor motion result in less than 2% of the tumor outside of the planning target volume (PTV) when the patient is aligned using skin marks. In addition, we found that if respiratory gating is going to be used, it is most effective if used in conjunction with image-guided patient setup. From the third part, we successfully developed, validated, and implemented on a patient a technique for aligning a moving target prior to treatment to reduce the uncertainties in tumor location. ^ In conclusion, setup uncertainties and tumor motion are a significant problem when treating tumors located within the thoracic region. Image-guided patient setup in conjunction with treatment delivery using respiratory gating reduces these uncertainties in tumor locations. In doing so, margins around the tumor used to generate the PTV can be reduced, which may allow for dose escalation to the tumor. ^

Access to health care among children in the U.S.: Use of health inequalities measures to evaluate progress in reduction of disparities from 1997 to 2005

Much of the literature on disparities in access to health care among children has focused on measuring absolute and relative differences experienced by race/ethnic groups and, to a lesser extent, socioeconomic groups. However, it is not clear from existing literature how disparities in access to care may have changed over time for children, especially following implementation of the State Children’s Health Insurance Program (SCHIP). The primary objective of this research was to determine if there has been a decrease in disparities in access to care for children across two socioeconomic groups and race/ethnicity groups after SCHIP implementation. Methods commonly used to measure ‘health inequalities’ were used to measure disparities in access to care including population-attributable risk (PAR) and the relative index of inequality (RII). Using these measures there is evidence of a substantial decrease in socioeconomic disparities in health insurance coverage and to a lesser extent in having a usual source of care since the SCHIP program began. There is also evidence of a considerable decrease in non-Hispanic Black disparities in access to care. However, there appears to be a slight increase in disparities in access to care among Hispanic compared to non-Hispanic White children. While there were great improvements in disparities in access to care with the introduction of the SCHIP program, continuing progress in disparities may depend on continuation of the SCHIP program or similar targeted health policy programs. ^

Implementation of active surveillance cultures and associated infection control practices for the reduction of methicillin resistant Staphylococcus aureus in the healthcare setting: An interrupted time series analysis

OBJECTIVE. To determine the effectiveness of active surveillance cultures and associated infection control practices on the incidence of methicillin resistant Staphylococcus aureus (MRSA) in the acute care setting. DESIGN. A historical analysis of existing clinical data utilizing an interrupted time series design. ^ SETTING AND PARTICIPANTS. Patients admitted to a 260-bed tertiary care facility in Houston, TX between January 2005 through December 2010. ^ INTERVENTION. Infection control practices, including enhanced barrier precautions, compulsive hand hygiene, disinfection and environmental cleaning, and executive ownership and education, were simultaneously introduced during a 5-month intervention implementation period culminating with the implementation of active surveillance screening. Beginning June 2007, all high risk patients were cultured for MRSA nasal carriage within 48 hours of admission. Segmented Poisson regression was used to test the significance of the difference in incidence of healthcare-associated MRSA during the 29-month pre-intervention period compared to the 43-month post-intervention period. ^ RESULTS. A total of 9,957 of 11,095 high-risk patients (89.7%) were screened for MRSA carriage during the intervention period. Active surveillance cultures identified 1,330 MRSA-positive patients (13.4%) contributing to an admission prevalence of 17.5% in high-risk patients. The mean rate of healthcare-associated MRSA infection and colonization decreased from 1.1 per 1,000 patient-days in the pre-intervention period to 0.36 per 1,000 patient-days in the post-intervention period (P<0.001). The effect of the intervention in association with the percentage of S. aureus isolates susceptible to oxicillin were shown to be statistically significantly associated with the incidence of MRSA infection and colonization (IRR = 0.50, 95% CI = 0.31-0.80 and IRR = 0.004, 95% CI = 0.00003-0.40, respectively). ^ CONCLUSIONS. It can be concluded that aggressively targeting patients at high risk for colonization of MRSA with active surveillance cultures and associated infection control practices as part of a multifaceted, hospital-wide intervention is effective in reducing the incidence of healthcare-associated MRSA.^

Evaluation of Polymer Gel Dosimeters for Measurements of Dose and LET in Proton Beams

This project assessed the effectiveness of polymer gel dosimeters as tools for measuring the dose deposited by and LET of a proton beam. A total of three BANG® dosimeter formulations were evaluated: BANG®-3-Pro-2 BANGkits™ for dose measurement and two BANG®-3 variants, the LET-Baseline and LET-Meter dosimeters, for LET measurement. All dosimeters were read out using an OCT scanner. The basic characteristics of the BANGkits™ were assessed in a series of photon and electron irradiations. The dose-response relationship was found to be sigmoidal with a threshold for response of approximately 15 cGy. The active region of the dosimeter, the volume in which dosimeter response is not inhibited by oxygen, was found to make up roughly one fourth of the total dosimeter volume. Delivering a dose across multiple fractions was found to yield a greater response than delivering the same dose in a single irradiation. The dosimeter was found to accurately measure a dose distribution produced by overlapping photon fields, yielding gamma pass rates of 95.4% and 93.1% from two planar gamma analyses. Proton irradiations were performed for measurements of proton dose and LET. Initial irradiations performed through the side of a dosimeter led to OCT artifacts. Gamma pass rates of 85.7% and 89.9% were observed in two planar gamma analyses. In irradiations performed through the base of a dosimeter, gel response was found to increase with height in the dosimeter, even in areas of constant dose. After a correction was applied, gamma pass rates of 94.6% and 99.3% were observed in two planar gamma analyses. Absolute dose measurements were substantially higher (33%-100%) than the delivered doses for proton irradiations. Issues encountered while calibrating the LET-Meter gel restricted analysis of the LET measurement data to the SOBP of a proton beam. LET-Meter overresponse was found to increase linearly with track-average LET across the LET range that could be investigated (1.5 keV/micron – 3.5 keV/micron).

BENCHMARKING AND IMPLEMENTATION OF A NEW INDEPENDENT MONTE CARLO DOSE CALCULATION QUALITY ASSURANCE AUDIT TOOL FOR CLINICAL TRIALS

Introduction Commercial treatment planning systems employ a variety of dose calculation algorithms to plan and predict the dose distributions a patient receives during external beam radiation therapy. Traditionally, the Radiological Physics Center has relied on measurements to assure that institutions participating in the National Cancer Institute sponsored clinical trials administer radiation in doses that are clinically comparable to those of other participating institutions. To complement the effort of the RPC, an independent dose calculation tool needs to be developed that will enable a generic method to determine patient dose distributions in three dimensions and to perform retrospective analysis of radiation delivered to patients who enrolled in past clinical trials. Methods A multi-source model representing output for Varian 6 MV and 10 MV photon beams was developed and evaluated. The Monte Carlo algorithm, know as the Dose Planning Method (DPM), was used to perform the dose calculations. The dose calculations were compared to measurements made in a water phantom and in anthropomorphic phantoms. Intensity modulated radiation therapy and stereotactic body radiation therapy techniques were used with the anthropomorphic phantoms. Finally, past patient treatment plans were selected and recalculated using DPM and contrasted against a commercial dose calculation algorithm. Results The multi-source model was validated for the Varian 6 MV and 10 MV photon beams. The benchmark evaluations demonstrated the ability of the model to accurately calculate dose for the Varian 6 MV and the Varian 10 MV source models. The patient calculations proved that the model was reproducible in determining dose under similar conditions described by the benchmark tests. Conclusions The dose calculation tool that relied on a multi-source model approach and used the DPM code to calculate dose was developed, validated, and benchmarked for the Varian 6 MV and 10 MV photon beams. Several patient dose distributions were contrasted against a commercial algorithm to provide a proof of principal to use as an application in monitoring clinical trial activity.

Long-lasting hyperexcitability induced by depolarization in the absence of detectable Ca2+ signals.

Learning and memory depend on neuronal alterations induced by electrical activity. Most examples of activity-dependent plasticity, as well as adaptive responses to neuronal injury, have been linked explicitly or implicitly to induction by Ca(2+) signals produced by depolarization. Indeed, transient Ca(2+) signals are commonly assumed to be the only effective transducers of depolarization into adaptive neuronal responses. Nevertheless, Ca(2+)-independent depolarization-induced signals might also trigger plastic changes. Establishing the existence of such signals is a challenge because procedures that eliminate Ca(2+) transients also impair neuronal viability and tolerance to cellular stress. We have taken advantage of nociceptive sensory neurons in the marine snail Aplysia, which exhibit unusual tolerance to extreme reduction of extracellular and intracellular free Ca(2+) levels. The axons of these neurons exhibit a depolarization-induced memory-like hyperexcitability that lasts a day or longer and depends on local protein synthesis for induction. Here we show that transient localized depolarization of these axons in an excised nerve-ganglion preparation or in dissociated cell culture can induce short- and intermediate-term axonal hyperexcitability as well as long-term protein synthesis-dependent hyperexcitability under conditions in which Ca(2+) entry is prevented (by bathing in nominally Ca(2+) -free solutions containing EGTA) and detectable Ca(2+) transients are eliminated (by adding BAPTA-AM). Disruption of Ca(2+) release from intracellular stores by pretreatment with thapsigargin also failed to affect induction of axonal hyperexcitability. These findings suggest that unrecognized Ca(2+)-independent signals exist that can transduce intense depolarization into adaptive cellular responses during neuronal injury, prolonged high-frequency activity, or other sustained depolarizing events.

Assessment of Collimator Jaw Optimization in Reducing Normal Tissue Irradiation with Intensity Modulated Radiation Therapy

Purpose: To evaluate normal tissue dose reduction in step-and-shoot intensity-modulated radiation therapy (IMRT) on the Varian 2100 platform by tracking the multileaf collimator (MLC) apertures with the accelerator jaws. Methods: Clinical radiation treatment plans for 10 thoracic, 3 pediatric and 3 head and neck patients were converted to plans with the jaws tracking each segment’s MLC apertures. Each segment was then renormalized to account for the change in collimator scatter to obtain target coverage within 1% of that in the original plan. The new plans were compared to the original plans in a commercial radiation treatment planning system (TPS). Reduction in normal tissue dose was evaluated in the new plan by using the parameters V5, V10, and V20 in the cumulative dose-volume histogram for the following structures: total lung minus GTV (gross target volume), heart, esophagus, spinal cord, liver, parotids, and brainstem. In order to validate the accuracy of our beam model, MLC transmission measurements were made and compared to those predicted by the TPS. Results: The greatest change between the original plan and new plan occurred at lower dose levels. The reduction in V20 was never more than 6.3% and was typically less than 1% for all patients. The reduction in V5 was 16.7% maximum and was typically less than 3% for all patients. The variation in normal tissue dose reduction was not predictable, and we found no clear parameters that indicated which patients would benefit most from jaw tracking. Our TPS model of MLC transmission agreed with measurements with absolute transmission differences of less than 0.1 % and thus uncertainties in the model did not contribute significantly to the uncertainty in the dose determination. Conclusion: The amount of dose reduction achieved by collimating the jaws around each MLC aperture in step-and-shoot IMRT does not appear to be clinically significant.

A novel treatment planning methodology for high dose 166Ho-DOTMP therapy in patients with multiple myeloma

Bone marrow ablation, i.e., the complete sterilization of the active bone marrow, followed by bone marrow transplantation (BMT) is a comment treatment of hematological malignancies. The use of targeted bone-seeking radiopharmaceuticals to selectively deliver radiation to the adjacent bone marrow cavities while sparing normal tissues is a promising technique. Current radiopharmaceutical treatment planning methods do not properly compensate for the patient-specific variable distribution of radioactive material within the skeleton. To improve the current method of internal dosimetry, novel methods for measuring the radiopharmaceutical distribution within the skeleton were developed. 99mTc-MDP was proven as an adequate surrogate for measuring 166Ho-DOTMP skeletal uptake and biodistribution, allowing these measures to be obtained faster, safer, and with higher spatial resolution. This translates directly into better measurements of the radiation dose distribution within the bone marrow. The resulting bone marrow dose-volume histograms allow prediction of the patient disease response where conventional organ scale dosimetry failed. They indicate that complete remission is only achieved when greater than 90% of the bone marrow receives at least 30 Gy. ^ Comprehensive treatment planning requires combining target and non-target organ dosimetry. Organs in the urinary tract were of special concern. The kidney dose is primarily dependent upon the mean transit time of 166 Ho-DOTMP through the kidney. Deconvolution analysis of renograms predicted a mean transit time of 2.6 minutes for 166Ho-DOTMP. The radiation dose to the urinary bladder wall is dependent upon numerous factors including patient hydration and void schedule. For beta-emitting isotopes such as 166Ho, reduction of the bladder wall dose is best accomplished through good patient hydration and ensuring a partially full bladder at the time of injection. Encouraging the patient to void frequently, or catheterizing the patient without irrigation, will not significantly reduce the bladder wall dose. ^ The results from this work will produce the most advanced treatment planning methodology for bone marrow ablation therapy using radioisotopes currently available. Treatments can be tailored specifically for each patient, including the addition of concomitant total body irradiation for patients with unfavorable dose distributions, to deliver a desired patient disease response, while minimizing the dose or toxicity to non-target organs. ^

A 3-D CT assisted Monte Carlo evaluation of intracavitary brachytherapy implants

Intracavitary brachytherapy (ICB) combined with external beam irradiation for treatment of cervical cancer is highly successful in achieving local control. The M.D. Anderson Cancer Center employs Fletcher Suit Delclos (FSD) applicators. FSD applicators contain shields to limit dose to critical structures. Dosimetric evaluation of ICB implants is limited to assessing dose at reference points. These points serve as surrogates for treatment intensity and critical structure dose. Several studies have mentioned that the ICRU38 reference points inadequately characterize the dose distribution. Also, the ovoid shields are rarely considered in dosimetry. ^ The goal of this dissertation was to ascertain the influence of the ovoid shields on patient dose distributions. Monte Carlo dosimetry (MCD) was applied to patient computed tomography(CT) scans. These data were analyzed to determine the effect of the shields on dose to standard reference points and the bladder and rectum. The hypothesis of this work is that the ICRU38 bladder and rectal points computed conventionally are not clinically acceptable surrogates for the maximum dose points as determined by MCD. ^ MCD was applied to the tandem and ovoids. The FSD ovoids and tandem were modeled in a single input file that allowed dose to be calculated for any patient. Dose difference surface histograms(DDSH) were computed for the bladder and rectum. Reference point doses were compared between shielded and unshielded ovoids, and a commercial treatment planning system. ^ The results of this work showed the tandem tip screw caused a 33% reduction in dose. The ovoid shields reduced the dose by a maximum of 48.9%. DDSHs revealed on average 5% of the bladder surface area was spared 53 cGy and 5% of the rectal surface area was spared 195 cGy. The ovoid shields on average reduced the dose by 18% for the bladder point and 25% for the rectal point. The Student's t-test revealed the ICRU38 bladder and rectal points do not predict the maximum dose for these organs. ^ It is concluded that modeling the tandem and ovoid internal structures is necessary for accurate dose calculations, the bladder shielding segments may not be necessary, and that the ICRU38 bladder point is irrelevant. ^

Maternal ingestion of radon-222 in drinking water and the absorbed radiation dose to the embryo

Maternal ingestion of high concentrations of radon-222 (Rn-222) in drinking during pregnancy may pose a significant radiation hazard to the developing embryo. The effects of ionizing radiation to the embryo and fetus have been the subject of research, analyses, and the development of a number of radiation dosimetric models for a variety of radionuclides. Currently, essentially all of the biokinetic and dosimetric models that have been developed by national and international radiation protection agencies and organizations recommend calculating the dose to the mother's uterus as a surrogate for estimating the dose to the embryo. Heretofore, the traditional radiation dosimetry models have neither considered the embryo a distinct and rapidly developing entity, the fact that it is implanted in the endometrial layer of the uterus, nor the physiological interchanges that take place between maternal and embryonic cells following the implantation of the blastocyst in the endometrium. The purpose of this research was to propose a new approach and mathematical model for calculating the absorbed radiation dose to the embryo by utilizing a semiclassical treatment of alpha particle decay and subsequent scattering of energy deposition in uterine and embryonic tissue. The new approach and model were compared and contrasted with the currently recommended biokinetic and dosimetric models for estimating the radiation dose to the embryo. The results obtained in this research demonstrate that the estimated absorbed dose for an embryo implanted in the endometrial layer of the uterus during the fifth week of embryonic development is greater than the estimated absorbed dose for an embryo implanted in the uterine muscle on the last day of the eighth week of gestation. This research provides compelling evidence that the recommended methodologies and dosimetric models of the Nuclear Regulatory Commission and International Commission on Radiological Protection employed for calculating the radiation dose to the embryo from maternal intakes of radionuclides, including maternal ingestion of Rn-222 in drinking water would result in an underestimation of dose. ^

The imaging and dosimetric capabilities of a CT/MR-suitable, anatomically adaptive, shielded intracavitary brachytherapy applicator for the treatment of cervical cancer

Introduction. Investigations into the shortcomings of current intracavitary brachytherapy (ICBT) technology has lead us to design an Anatomically Adaptive Applicator (A3). The goal of this work was to design and characterize the imaging and dosimetric capabilities of this device. The A3 design incorporates a single shield that can both rotate and translate within the colpostat. We hypothesized that this feature, coupled with specific A3 component construction materials and imaging techniques, would facilitate artifact-free CT and MR image acquisition. In addition, by shaping the delivered dose distribution via the A3 movable shield, dose delivered to the rectum will be less compared to equivalent treatments utilizing current state-of-the-art ICBT applicators. ^ Method and materials. A method was developed to facilitate an artifact-free CT imaging protocol that used a "step-and-shoot" technique: pausing the scanner midway through the scan and moving the A 3 shield out of the path of the beam. The A3 CT imaging capabilities were demonstrated acquiring images of a phantom that positioned the A3 and FW applicators in a clinically-applicable geometry. Artifact-free MRI imaging was achieved by utilizing MRI-compatible ovoid components and pulse-sequences that minimize susceptibility artifacts. Artifacts were qualitatively compared, in a clinical setup. For the dosimetric study, Monte-Carlo (MC) models of the A3 and FW (shielded and unshielded) applicators were validated. These models were incorporated into a MC model of one cervical cancer patient ICBT insertion, using 192Ir (mHDR v2 source). The A3 shield's rotation and translation was adjusted for each dwell position to minimize dose to the rectum. Superposition of dose to rectum for all A3 dwell sources (4 per ovoid) was applied to obtain a comparison of equivalent FW treatments. Rectal dose-volume histograms (absolute and HDR/PDR biologically effective dose (BED)) and BED to 2 cc (BED2cc ) were determined for all applicators and compared. ^ Results. Using a "step-and-shoot" CT scanning method and MR compliant materials and optimized pulse-sequences, images of the A 3 were nearly artifact-free for both modalities. The A3 reduced BED2cc by 18.5% and 7.2% for a PDR treatment and 22.4% and 8.7% for a HDR treatment compared to treatments delivered using an uFW and sFW applicator, respectively. ^ Conclusions. The novel design of the A3 facilitated nearly artifact-free image quality for both CT and MR clinical imaging protocols. The design also facilitated a reduction in BED to the rectum compared to equivalent ICBT treatments delivered using current, state-of-the-art applicators. ^

Design of long-term animal bioassay for low-dose extrapolation using a multistage model

Conventional designs of animal bioassays allocate the same number of animals into control and dose groups to explore the spontaneous and induced tumor incidence rates, respectively. The purpose of such bioassays are (a) to determine whether or not the substance exhibits carcinogenic properties, and (b) if so, to estimate the human response at relatively low doses. In this study, it has been found that the optimal allocation to the experimental groups which, in some sense, minimize the error of the estimated response for low dose extrapolation is associated with the dose level and tumor risk. The number of dose levels has been investigated at the affordable experimental cost. The pattern of the administered dose, 1 MTD, 1/2 MTD, 1/4 MTD,....., etc. plus control, gives the most reasonable arrangement for the low dose extrapolation purpose. The arrangement of five dose groups may make the highest dose trivial. A four-dose design can circumvent this problem and has also one degree of freedom for testing the goodness-of-fit of the response model.^ An example using the data on liver tumors induced in mice in a lifetime study of feeding dieldrin (Walker et al., 1973) is implemented with the methodology. The results are compared with conclusions drawn from other studies. ^

THE RELATIONSHIP BETWEEN DEGREE OF BLOOD PRESSURE REDUCTION AND MORTALITY AMONG HYPERTENSIVES IN THE HYPERTENSION DETECTION AND FOLLOW-UP PROGRAM

The relationship between degree of diastolic blood pressure (DBP) reduction and mortality was examined among hypertensives, ages 30-69, in the Hypertension Detection and Follow-up Program (HDFP). The HDFP was a multi-center community-based trial, which followed 10,940 hypertensive participants for five years. One-year survival was required for inclusion in this investigation since the one-year annual visit was the first occasion where change in blood pressure could be measured on all participants. During the subsequent four years of follow-up on 10,052 participants, 568 deaths occurred. For levels of change in DBP and for categories of variables related to mortality, the crude mortality rate was calculated. Time-dependent life tables were also calculated so as to utilize available blood pressure data over time. In addition, the Cox life table regression model, extended to take into account both time-constant and time-dependent covariates, was used to examine the relationship change in blood pressure over time and mortality.^ The results of the time-dependent life table and time-dependent Cox life table regression analyses supported the existence of a quadratic function which modeled the relationship between DBP reduction and mortality, even after adjusting for other risk factors. The minimum mortality hazard ratio, based on a particular model, occurred at a DBP reduction of 22.6 mm Hg (standard error = 10.6) in the whole population and 8.5 mm Hg (standard error = 4.6) in the baseline DBP stratum 90-104. After this reduction, there was a small increase in the risk of death. There was not evidence of the quadratic function after fitting the same model using systolic blood pressure. Methodologic issues involved in studying a particular degree of blood pressure reduction were considered. The confidence interval around the change corresponding to the minimum hazard ratio was wide and the obtained blood pressure level should not be interpreted as a goal for treatment. Blood pressure reduction was attributed, not only to pharmacologic therapy, but also to regression to the mean, and to other unknown factors unrelated to treatment. Therefore, the surprising results of this study do not provide direct implications for treatment, but strongly suggest replication in other populations. ^

The assumptions and effects of conservative procedures in low -dose risk assessment for setting safety standards

Conservative procedures in low-dose risk assessment are used to set safety standards for known or suspected carcinogens. However, the assumptions upon which the methods are based and the effects of these methods are not well understood.^ To minimize the number of false-negatives and to reduce the cost of bioassays, animals are given very high doses of potential carcinogens. Results must then be extrapolated to much smaller doses to set safety standards for risks such as one per million. There are a number of competing methods that add a conservative safety factor into these calculations.^ A method of quantifying the conservatism of these methods was described and tested on eight procedures used in setting low-dose safety standards. The results using these procedures were compared by computer simulation and by the use of data from a large scale animal study.^ The method consisted of determining a "true safe dose" (tsd) according to an assumed underlying model. If one assumed that Y = the probability of cancer = P(d), a known mathematical function of the dose, then by setting Y to some predetermined acceptable risk, one can solve for d, the model's "true safe dose".^ Simulations were generated, assuming a binomial distribution, for an artificial bioassay. The eight procedures were then used to determine a "virtual safe dose" (vsd) that estimates the tsd, assuming a risk of one per million. A ratio R = ((tsd-vsd)/vsd) was calculated for each "experiment" (simulation). The mean R of 500 simulations and the probability R $<$ 0 was used to measure the over and under conservatism of each procedure.^ The eight procedures included Weil's method, Hoel's method, the Mantel-Byran method, the improved Mantel-Byran, Gross's method, fitting a one-hit model, Crump's procedure, and applying Rai and Van Ryzin's method to a Weibull model.^ None of the procedures performed uniformly well for all types of dose-response curves. When the data were linear, the one-hit model, Hoel's method, or the Gross-Mantel method worked reasonably well. However, when the data were non-linear, these same methods were overly conservative. Crump's procedure and the Weibull model performed better in these situations. ^