Search PubMed⌕ Search

Biomedical subjects

T D Jones

Publications and source records attributed to T D Jones.

At least 55 records · Page 3Linked to original sources
PubMed1993

Mathematical models of marrow cell kinetics: differential effects of protracted irradiations on stromal and stem cells in mice.

UNLABELLED: It is known that hematopoiesis is supported by bone-marrow stem cells, but those cells must seed and grow on a stromal microenvironment. Typically, studies have shown that a surviving fraction of about 30 hematopoietic stem cells (HSCs) (i.e., about 0.04%) correspond to the LD50, although other studies have shown that marrow can repopulate from a single viable cell under strong regiments of antibiotics and infusions of irradiated blood elements. PURPOSE: This paper describes comparisons between our results (from maximum-likelihood estimation techniques for cellular damage, repair, and compensatory repopulation) and published experimental data on marrow stromal cells. METHODS AND MATERIALS: After biophysical consideration of the rate constants that were derived by maximizing the likelihood function (a consideration necessary to extend the model to cell populations not indicated by the model as "critical" for recovery), the rate constants for cellular damage to stem cells are fitted to experimental data. Rate constants for repair and proliferation of stem cells are assigned based on published data on repair/proliferation half-times, and these assignments affect the evaluation of the rate constants for cellular damage. From the two models, that is one for "critical" cells (having radiosensitive and repopulation characteristics similar to stromal cells) and another for stem cells, effects on two cell populations of different radiosensitivities and repopulation rates can be demonstrated for complex schedules of protracted irradiations which could reduce either cell population below a critical need for marrow repopulation. RESULTS: Our analysis of animal mortality data has indicated that recovery of an animal from potentially lethal irradiation is dominantly regulated by cells with survival and repopulation characteristics similar to those of stroma cells. CONCLUSION: In contrast to the surviving fraction of hematopoietic stem cells, it appears that the probability of an animal's recovery is high if the "critical" population of cells is above 1% (our "best" maximum likelihood estimate, from mouse data, with the corresponding lower confidence bound at about 0.2%). Of course, a few stem cells--perhaps only one--must maintain a potential for repopulation of blood and marrow.

Animals↗
PubMed1993

A cell kinetics model of radiation-induced myelopoiesis: rate coefficient estimates for mouse, rat, sheep, swine, dog, and burro irradiated by photons.

Rate coefficients in the model of cell kinetics and mortality introduced by Jones et al. (Radiat. Res. 128, 258-266, 1991) are estimated using mortality data from 27 animal experiments. Adjustments are made for the six species and three nominal classes of gamma radiation represented in these studies. The model fits most of the mortality data quite well when the rate coefficient representing cellular proliferation is fitted to individual species and each of the other coefficients is given a single value across the entire data set. Results are qualitatively similar to those reported by Morris et al. (Radiat. Res. 128, 267-275, 1991) who estimated the rate coefficients from a limited number of mouse studies involving only 250 kVp X rays. As in the earlier study, estimates here lead to greater cell survival than is observed for marrow cells in the amplification division compartment.

Animals↗
PubMed1993

A cell-kinetics model for radiation-induced myelopoiesis.

A mathematical model of time-dependent cellular damage, repair, killing and repopulation of bone marrow following treatments with ionizing radiations is described. Effects from variable dose rates, multiple exposures, different radiation sources and arbitrary intervals between treatments can be modeled by ordinary differential equations. Of several unique features, the most unusual is that rate constants for injury, repair, killing and proliferation of cells are evaluated by likelihood analysis of animal mortality data. Results indicate that a relatively radioresistant pool of bone marrow cells mediates the proliferation of the hematopoietic stem cells. Applications include modeling of 1) myelopoietic integrity as a function of time and dose rate, 2) the whole-body survival curve (at any point in the treatment protocol) for cells critical to myelopoiesis, 3) a prompt dose equivalence from any completed portion of a therapeutic schedule and 4) potential gain from schedule changes during the course of the treatment.

Animals↗
PubMed1992

Relative potency estimates of acceptable residues and reentry intervals after nerve agent release.

In the event of an unplanned release of a chemical warfare agent during any stage of the Chemical Stockpile Disposal Program, the potential exists for off-post contamination of drinking water, forage crops, grains, garden produce, and livestock. The more persistent agents, such as the organophosphate nerve agent VX, pose the greatest human health concern for reentry. A relative potency approach comparing the toxicity of VX to organophosphate insecticide analogues is developed and used to estimate allowable residues for VX in agricultural products and reentry intervals for public access to contaminated areas. Analysis of mammalian LD50 data by all exposure routes indicates that VX is 10(3) to 10(4) times more toxic than most commercially available organophosphate insecticides. Thus, allowable residues of VX could be considered at concentration levels 10(3) to 10(4) lower than those established for certain insecticides by the U.S. EPA. Evaluation of reentry intervals developed for these organophosphate analogues indicate that, if environmental monitoring cannot reliably demonstrate acceptable levels of VX, restricted access to suspect or contaminated areas may be on the order of weeks to months following agent release. Planning for relocation, mass care centers, and quarantine should take this time period into account.

Chemical Warfare Agents↗
PubMed1991

Ranking of carcinogenic potency using a relative potency approach.

Protocols for long-term carcinogen bioassays have become highly refined. The ability to interpret these bioassay results beyond the experimental setting, however, has not improved commensurately. As a consequence, society is still faced with the fact that data derived in these bioassays reflect highly specific experimental conditions which are vastly different from environmental exposures of the freely roaming, outbred human. The scientific community has responded with a "collective wisdom" approach by using expert committees to interpret bioassay evidence. This committee approach is believed to be successful in protecting human health, but the list of suspected carcinogens is growing faster than the expert committees can respond. We have developed a relative potency framework for ranking the hazards represented by potential human carcinogens. The results demonstrate a rank ordering of a variety of compounds which is independent of the reference compound used to standardize the information. The philosophic basis of the approach may facilitate expert risk assessment systems development because it: (1) complements and supports "expert committee" data selection; (2) has a simple set of rules and does not require mathematical modeling; (3) requires no special situation judgments; and (4) is suitable for use with electronic data bases.

Animals↗
PubMed1991

Protection of human health from mixtures of radionuclides and chemical in drinking water.

This study was undertaken to develop a common scale for evaluating health risks from contaminated drinking water. For different agents, many unrealistic models of risk have been used. By intent, regulatory toxicology depends on "data-sparse, model-intensive" analogies from exotic animal genetics and novel exposures (NCRP 1989). The question is, does a risk evaluation so derived have any predictive validity? Absence of data prevents answer because regulatory toxicology rationalizes in step-by-step logic, which we call absolute (i.e., predicts cases of disease in a population). Absolute models ensure safety, but do so at the cost of realism. In contrast, we make relative comparisons in the manner of horsepower or RBE from radiation biology. All pollutants are assumed to contribute to toxic injury. Next, relative potencies are linked to the most credible standards. Thus, experience is transferred from well-studied chemicals to the new chemical by "data-intensive, model-sparse" methods. This logos provides much relative precision. Then, pollutants are compared with: (1) common foodstuffs, (2) ambient radiation background, or (3) utility-pure drinking water. Finally, an assessment is made for a waste disposal area.

Carcinogens↗
PubMed1991

The detection of beet western yellows virus and beet mild yellowing virus in crop plants using the polymerase chain reaction.

Oligonucleotide primers were synthesised corresponding to conserved sequences between three isolates of beet western yellows virus (BWYV), flanking a 913 base fragment of BWYV genomic RNA. Using the polymerase chain reaction (PCR), these primers successfully amplified the target fragment in total RNA extracts from two oilseed rape plants infected with different isolates of BWYV. The PCR products were readily detected by staining with ethidium bromide following agarose gel electrophoresis, but the limit of detection could be increased further by Southern blotting. However, three isolates of beet mild yellowing virus (BMYV) in sugar beet did not give a signal which could be detected by ethidium bromide staining, although the target fragment could be detected by Southern blotting. The primers used have the potential to detect BWYV in crops with far greater sensitivity than enzyme-linked immunosorbent assay or nucleic acid hybridisation (dot-blotting) and may be capable of distinguishing between BWYV and BMYV. The application of PCR to detection and distinction of luteoviruses in general is discussed.

Base Sequence↗
PubMed1991

On the rodent bioassays currently being conducted on 44 chemicals: a RASH analysis to predict test results from the National Toxicology Program.

We use a method of relative potency comparisons to rank the potential strength of 44 compounds being tested in rodent carcinogenicity bioassays. All of our previous hazard evaluations have been for human conditions where great numbers of simultaneous and serial exposures may act in combination to produce a neoplasm comprised of 2(20) to 2(30) cells commonly expected to derive from a single precancerous cell. For human exposures, we have always assumed an initiated target tissue containing at least one transformed but subcarcinogenic cell per organ. Thus, for man we have focused on empirical correspondences that may help to index the monoclonal growth of a particular cell lineage during cancer expansion. In contrast to humans, initiation of target tissues in animals subjected to National Toxicity Program (NTP) bioassays may not be a given condition, because of extensive precautions taken to minimize exposures to contaminates in food, water and cage environments. For this evaluation, we used categorical assignments of 'unlikely', 'possible' and 'probable' carcinogens adapted from NTP tests. Our rank ordering, of compounds according to maximum doses tested in male mice and male rats, is coded accordingly to the three outcomes taken from the NTP tests, but the magnitude of potency depend completely upon our particular method of comparing toxicological data. We have attempted to demonstrate that a relative potency based analysis of a diversity of toxicological data may be useful for rank ordering potentially hazardous compounds to be tested by the NTP and for range-finding of their effective test doses to be administered during chronic test protocols.

Animals↗
PubMed1991

A mathematical model for radiation-induced myelopoiesis.

A model for damage, repair, killing, and repopulation of myelopoietic marrow is presented. Evaluation produces time and dose-rate profiles during and following any complex irradiation. Equations model variable dose rates, multiple exposures, different sources, and arbitrary intervals between treatments. If factors which dominate the control of biological processes can be demonstrated, an option is to set biological rate constants to experimentally determined values. Previously, knowledge did not permit identification of dominating biological processes and their temporal rates. But a unique feature of this study is that unspecified lesions for killing and injury of cells are evaluated from mortality data on the animal species of choice. "Unspecified" is used to indicate a condition of assumption-free modeling of molecular processes, whereby rate constants for cellular effects are simply computed directly from animal mortality data. Coefficients (estimated by maximum-likelihood methods for nonspecific processes) are compared with experimental values for specific processes. The model has many uses, including modeling of the myelopoietic potential as a function of time. Another option is to calculate the whole-body survival curve for cells that control myelopoiesis as a result of the treatment schedule. Also through simple extensions of the model, an extremely complex protocol can be identified with an equivalent prompt dose value--even for partial-body, fractionated exposures.

Animals↗
PubMed1991

Estimation of coefficients in a model of radiation-induced myelopoiesis from mortality data for mice following X-ray exposure.

The rate coefficients in the model of cell kinetics and mortality introduced by Jones et al. (Radiat. Res. 128, 258-266 (1991)) are estimated using mortality data from several mouse experiments. The evaluated model fits data from a large variety of prompt, protracted, and fractionated irradiations with 250-k Vp X rays with good fidelity. Although the maximum-likelihood estimates are not unique, all estimates lead to greater cell survival than that observed in in vitro experiments on nonterminally differentiated reproducing cells from the marrow.

Animals↗
PubMed1990

Hazard evaluation for complex mixtures: relative comparisons to improve regulatory consistency.

The traditional "absolute decision-making" process used by federal regulatory agencies to derive permissible exposure concentrations for hazardous substances is initiated by an evaluation of the "weight-of-evidence" that a substance is a potential human carcinogen. Subsequent conservative procedures applied variably to noncarcinogens and carcinogens yield exposure limits for individual substances based on "data-sparse, model-intensive" techniques which may lack consistency and have difficulty directly addressing the hazards from complex mixtures. This paper describes how a "relative decision-making" technique applicable to complex mixtures can supplement the "absolute" approach currently used. Estimates obtained through this "data-intensive, model-sparse" technique may be evaluated by comparisons to estimates representing a range of hazards "generally regarded as safe" derived through analyses of chlorinated drinking water, cigarette smoke condensate, and other common human exposures. Comparisons are also used to evaluate the relative degree of consistency in risk estimates between 58 suspect human carcinogens analyzed by the U.S. Environmental Protection Agency Carcinogen Assessment Group and by the authors.

Animals↗
PubMed1989

Sulfur mustard as a carcinogen: application of relative potency analysis to the chemical warfare agents H, HD, and HT.

A relative potency method for assessing potential human health effects from exposures to relatively untested chemicals is presented and documented. The need for such a method in evaluating the carcinogenic potential of the chemical warfare agent sulfur mustard (agent HD) from a limited data base is specifically addressed. The best-estimate potency factor for sulfur mustard relative to benzo[a]pyrene is 1.3, with an interquartile range of 0.6 to 2.9. The method is applied to (1) the estimated fence-boundary air concentrations of mustard during operation of a proposed agent incinerator at Aberdeen Proving Ground (APG), Maryland, and (2) the current approved general population exposure level of 1 X 10(-4) mg HD/m3 and the occupational exposure level of 3 X 10(-3) mg HD/m3. Maximum estimates of excess lifetime cancer risk for individuals at sites along the APG boundary range between 3 X 10(-8) and 1 X 10(-7). Lifetime cancer risk estimates less than or equal to 10(-6) are not now regulated by the U.S. Environmental Protection Agency or the Food and Drug Administration. Maximum estimates of excess lifetime cancer risk assuming daily exposure to the approved standards during the proposed 5 years of incinerator operation are on the order of 10(-5) for the general public and 10(-4) for the worker population. These values are considered upper limit estimates.

Animals↗
PubMed1989

The repeatability and validity of respiratory resistance measured by the forced oscillation technique.

Measurement of forced expiratory volume in one second (FEV1) is commonly used in bronchial challenge testing in laboratory and epidemiological studies but has certain disadvantages. We have therefore studied the repeatability and validity of a derived measurement of respiratory resistance (Ros) obtained with the Siregnost FD5 impedance oscillometer (Siemens). Repeatability was estimated in 25 non-asthmatics and 28 asthmatics and compared with that of PEFR, FEV1 and specific conductance. PEFR and FEV1 were the most repeatable. Repeatability for measurements with the oscillometer as measured by the intraclass correlation coefficient for a single measurement was 0.75 for non-asthmatics, but was less good for asthmatics (intraclass correlation coefficient 0.56). To assess the validity of respiratory resistance measured during a histamine bronchial challenge test a sample of 20 hospital personnel was studied on four occasions, FEV1 and Ros both being measured twice. Ros changed at lower doses of histamine than FEV1, but the intraclass correlation coefficient for repeatability of change only reached 0.6 at an absolute dose of 3.41 mumol histamine. The estimated provocation dose of histamine producing a 35% fall in Ros was 8.70 mumol (95% range for a single measurement +/- 1.11 doubling doses), that producing a 10% fall in FEV1 was 8.32 mumol (95% range +/- 1.04 doubling doses) and a 20% fall in FEV1 11.48 mumol (95% range +/- 1.11 doubling doses). Measurements obtained with the Siregnost FD5 oscillometer are repeatable. The use of Ros during bronchial challenge testing is valid, but shows insufficient advantage over FEV1 to support its use in epidemiological studies.

Adult↗
PubMed1989

Hematopoietic death of unprotected man from photon irradiations: statistical modeling from animal experiments.

Most estimates of the radiation dose lethal to 50 per cent of a human population are based on historical data taken from well-known experiences reflecting inadequately known physical and biological conditions, or from medical procedures where individual patients received advantages of modern clinical care. It has been debated as to whether the experience of unprotected man would more closely reflect that of hospital patients or of the radiobiological studies with large animals. The issue at question is whether the apparent two-fold or more increased susceptibility of large animals to death from bone marrow damage (compared with the majority of estimates for man) is due more to true interspecies differences or the lack of medical support. This study is an attempt to assess the radiosensitivity of unprotected man in terms of the composite animal experiments. Based upon an extensive data base containing 121 separate animals studies using 13 different species, an estimate of the mortality dose-response relationship due to a uniform, continuous field of photon radiation is predicted for 70 kg unprotected man. Man is assumed to have a level of radiation sensitivity similar to that of the species represented in the data base, after adjustment for body weight. The mathematical model used includes fixed terms to account for effects of body weight and dose rate, and random terms reflecting inter- and intra-species variation and experimental error. Point predictions and 95 per cent prediction intervals are given for the LD05, LD10, LD25, LD50, LD75, LD90, and LD95, for dose rates ranging from 0.01 to 0.5 Gy/min, and treatment times ranging from about 2 min to about 24 h. At 1 cGy/min our point prediction of the LD50 is 299 cGy with an associated 95 per cent prediction interval of (168 cGy, 535 cGy). The analogous values at 50 cGy/min are 183 cGy and (103 cGy, 326 cGy).

Animals↗
PubMed1989

Effect of changing dietary sodium on the airway response to histamine.

The airway response to histamine has been shown to be related to the 24 hour urinary excretion of sodium. To assess whether this relation is likely to represent a direct causal association a randomised double blind crossover trial of slow sodium (80 mmol/day) was compared with placebo in 36 subjects having a low sodium diet. The dose of histamine causing a 20% fall in FEV1 (PD20) was 1.51 doubling doses lower when the men were taking sodium than when they were taking placebo (p less than 0.05). On the basis of PD10 values, the difference in men was 1.66 doubling doses of histamine (p less than 0.05). There was no corresponding effect in women. Regressing PD10 against urinary excretion of electrolytes with data from the two occasions during the trial and the measurements made before the trial showed a significant association with sodium excretion after allowance had been made for any effect associated with potassium or creatinine excretion, the latter being a marker of the completeness of the urine collection. Again there was no corresponding effect among women. These findings are compatible with the differences in regional mortality data for England and Wales, which show a relation between asthma mortality and regional per person purchases of table salt for men but not for women.

Adult↗
PubMed1989

The distribution of peak expiratory flow variability in a population sample.

Although serial peak expiratory flow (PEF) measurements are often used to assess the variability of airflow obstruction, the range of values to be expected in the general population has never been defined, nor is there any consensus as to how PEF variability should be expressed. We have compared PEF recordings made by 121 subjects selected at random from the population of a small town (Group A) and 221 subjects selected because of wheeze in the last year (Group B). Subjects were asked to record PEF every 2 h during waking hours for 7 days using a mini-Wright peak flow meter. Seven indices of PEF variability were derived for each subject and the range for each index determined. All indices showed a positively skewed distribution in the random sample. Two variability indices, standard deviation percent mean and amplitude percent mean, provided the greatest separation between subjects with both a diagnosis of asthma and wheeze in the last year and subjects with neither feature and also provided the highest intra-class correlation coefficients. We conclude that amplitude percent mean and standard deviation percent mean provide the best means of expressing PEF variability for epidemiological purposes, but that amplitude percent mean is more easily derived and appears to be the index of choice. PEF variability has a continuous distribution in the general population and no clear-cut division between asthmatic and nonasthmatic subjects can be defined.

Adolescent↗