Use of fractional polynomials for dose-response modelling and quantitative                 risk assessment in developmental toxicity studies

Developmental toxicity studies are an important area in the field of toxicology. Endpoints measured on fetuses include weight and indicators of death and malformation. Binary indicator measures are typically summed over the litter and a discrete distribution is assumed to model the number of adversely affected fetuses. Additionally, there is noticeable variation in the litter responses within dose groups that should be taken into account when modeling. Finally, the dose-response pattern in these studies exhibits a threshold effect. The threshold dose-response model is the default model for non-carcinogenic risk assessment, according to the USEPA, and is encouraged by the agency for the use in the risk assessment process. Two statistical models are proposed to estimate dose-response pattern of data from the developmental toxicity study: the threshold model and the spline model. The models were applied to two data sets. The advantages and disadvantages of these models, potential other models, and future research possibilities will be summarized.

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A litter-based approach to risk assessment in developmental toxicity studies via a power family of completely monotone functions

Journal of the Royal Statistical Society Series C (Applied Statistics) ◽

10.1046/j.1467-9876.2003.05369.x ◽

2004 ◽

Vol 53 (2) ◽

pp. 369-386 ◽

Cited By ~ 14

Author(s):

Anthony Y. C. Kuk

Keyword(s):

Risk Assessment ◽

Developmental Toxicity ◽

Monotone Functions ◽

Completely Monotone Functions ◽

Toxicity Studies ◽

Completely Monotone

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Application of a Framework for Grouping and Mixtures Toxicity Assessment of PFAS: A Closer Examination of Dose-Additivity Approaches

Toxicological Sciences ◽

10.1093/toxsci/kfaa123 ◽

2020 ◽

Author(s):

Philip E Goodrum ◽

Janet K Anderson ◽

Anthony L Luz ◽

Graham K Ansell

Keyword(s):

Risk Assessment ◽

Carboxylic Acids ◽

Dose Response ◽

Sulfonic Acid ◽

Hazard Index ◽

Mixture Toxicity ◽

Response Curves ◽

Toxicity Studies ◽

Data Gaps ◽

Dose Response Curves

Abstract Environmental occurrence and biomonitoring data for per- and polyfluoroalkyl substances (PFAS) demonstrate that humans are exposed to mixtures of PFAS. This article presents a new and systematic analysis of available PFAS toxicity study data using a tiered mixtures risk assessment framework consistent with United States and international mixtures guidance. The lines of evidence presented herein include a critique of whole mixture toxicity studies and analysis of dose-response models based on data from subchronic oral toxicity studies in rats. Based on available data to-date, concentration addition and relative potency factor methods are found to be inappropriate due to differences among sensitive effects and target organ potencies and noncongruent dose-response curves for the same effect endpoints from studies using the same species and protocols. Perfluorooctanoic acid and perfluorooctane sulfonic acid lack a single mode of action or molecular initiating event and our evaluation herein shows they also have noncongruent dose-response curves. Dose-response curves for long-chain perfluoroalkyl sulfonic acids (PFSAs) also significantly differ in shapes of the curves from short-chain PFSAs and perfluoroalkyl carboxylic acids evaluated, and additional differences are apparent when curves are evaluated based on internal or administered dose. Following well-established guidance, the hazard index method applied to perfluoroalkyl carboxylic acids and PFSAs grouped separately is the most appropriate approach for conducting a screening level risk assessment for nonpolymeric PFAS mixtures, given the current state-of-the science. A clear presentation of assumptions, uncertainties, and data gaps is needed before dose-additivity methods, including hazard index , are used to support risk management decisions. Adverse outcome pathway(s) and mode(s) of action information for perfluorooctanoic acid and perfluorooctane sulfonic acid and for other nonpolymer PFAS are key data gaps precluding more robust mixtures methods. These findings can guide the prioritization of future studies on single chemical and whole mixture toxicity studies.

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Quantitative risk assessment of Bacillus cereus in pasteurised milk produced in the Slovak Republic

Czech Journal of Food Sciences ◽

10.17221/106/2013-cjfs ◽

2014 ◽

Vol 32 (No. 2) ◽

pp. 122-131 ◽

Cited By ~ 4

Author(s):

P. Ačai ◽

Ľ. Valík ◽

D. Liptáková

Keyword(s):

Risk Assessment ◽

Bacillus Cereus ◽

Exposure Assessment ◽

Dose Response ◽

Slovak Republic ◽

Reporting Rate ◽

Assessment Model ◽

Quantitative Risk Assessment ◽

Milk Consumption ◽

Using Data

Quantitative risk assessment of Bacillus cereus using data from pasteurised milk produced in Slovakia was performed. Monte Carlo simulations were used for probability calculation of B. cereus density at the time of pasteurised milk consumption for several different scenarios. The results of the general case exposure assessment indicated that almost 14% of cartons can contain > 10<sup>4</sup> CFU/ml of B. cereus at the time of pasteurised milk consumption. Despite the absence of a generally applicable dose-response relationship that limits a full risk assessment, the probability of intoxication per serving and the estimated number of cases in the population were calculated for the general exposure assessment scenario using an exponential dose-response model based on Slovak data. The mean number of annual cases provided by the risk assessment model for pasteurised milk produced in Slovakia was 0.054/100 000 population. In comparison, the overall reporting rate of the outbreaks in the EU in which B. cereus toxins were the causative agent was 0.02/100 000 population in 2010. Our assessment is in accordance with a generally accepted fact that reporting data for alimentary intoxication are underestimated, mostly due to the short duration of the illness.  

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Quantitative Risk Assessment for Viral Contamination of Shellfish and Coastal Waters

Journal of Food Protection ◽

10.4315/0362-028x-56.12.1043 ◽

1993 ◽

Vol 56 (12) ◽

pp. 1043-1050 ◽

Cited By ~ 43

Author(s):

JOAN B. ROSE ◽

MARK D. SOBSEY

Keyword(s):

Risk Assessment ◽

Dose Response ◽

Probability Model ◽

Enteric Virus ◽

Epidemiological Data ◽

The United States ◽

Hazard Identification ◽

Quantitative Risk Assessment ◽

Individual Risk ◽

Viral Contamination

Human pathogenic viruses have been detected from approved shellfish harvesting waters based on the fecal coliform indicator. Until recently it was difficult to assess viral contamination and the potential impact on public health. Risk assessment is a valuable tool which can be used to estimate adverse effects associated with microbial hazards. This report describes the use of quantitative risk assessment for evaluating potential human health impacts associated with exposure to viral contamination of shellfish. The four fundamental steps used in a formal risk assessment are described within and include i) Hazard identification, ii) Dose-response determination, iii) Exposure assessment, and iv) Risk characterization. Dose-response models developed from human feeding studies were used to evaluate the risk of infection from contaminated shellfish. Of 58 pooled samples, 19% were found to be positive for viruses. Using an echovirus-12 probability model, the individual risk was determined for consumption of 60 g of raw shellfish. Individual risks ranged from 2.2 × 10−4 to 3.5 × 10−2. These data suggest that individuals consuming raw shellfish from approved waters in the United States may have on the average a 1 in 100 chance of becoming infected with an enteric virus. Using the rotavirus model which represents a more infectious virus, the risk rose to 5 in 10. The potential for use of a risk assessment approach for developing priorities and strategies for control of disease is immense. Epidemiological data have demonstrated the significance of shellfish-associated viral disease and, although limited, appropriate virus occurrence data are available. Additional information on virus occurrence and exposure is needed, and then scientific risk assessment can be used to better assure the safety of seafood.

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Signal management in pharmacovigilance and human risk assessment of CpG 7909, integrating embryo-fetal and post-natal developmental toxicity studies in rats and rabbits

Reproductive Toxicology ◽

10.1016/j.reprotox.2017.09.006 ◽

2018 ◽

Vol 75 ◽

pp. 110-120 ◽

Cited By ~ 1

Author(s):

Frédérique Delannois ◽

Camille Planty ◽

Giulia Giordano ◽

Eric Destexhe ◽

Dinesh Stanislaus ◽

...

Keyword(s):

Risk Assessment ◽

Developmental Toxicity ◽

Human Risk Assessment ◽

Human Risk ◽

Toxicity Studies

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Some implications for quantitative risk assessment if hormesis exists

Human & Experimental Toxicology ◽

10.1177/096032719801700508 ◽

1998 ◽

Vol 17 (5) ◽

pp. 259-262 ◽

Cited By ~ 9

Author(s):

Robert L Sielken ◽

Donald E Stevenson

Keyword(s):

Risk Assessment ◽

Dose Level ◽

Dose Response ◽

Epidemiological Data ◽

Quantitative Risk Assessment ◽

Upper And Lower Bounds ◽

Weight Of Evidence ◽

Adverse Health Effects ◽

Response Information ◽

Relevant Dose

The existence of hormesis should impact quantitative risk assessment in at least seven fundamental ways. (1) The dose-reponse models for bioassay and epidemiological data should have greater flexibility to fit the observed shape of the dose-response data and no longer be forced to always be linearly increasing at low doses. (2) Experimental designs should be altered to provide greater opportunity to identify the hormetic component of a dose-response relationship. (3) Rather than a lifetime average daily dose or its analog for shorter time periods, dose scales or metrics should be used that reflect the age or time dependence of the dose level. (4) Low-dose risk characterization should include the likelihood of bene-ficial effects and the likelihood that a dose level has reasonable certainty of no appreciable adverse health effects. (5) Exposure assessments should make greater efforts to characterize the distribution of actual doses from exposure rather than just upper bounds. (6) Uncertainty characterizations should be expanded to include both upper and lower bounds, and there should be an increased explicit use of expert judgement and weight-of-evidence based distributional analyses reflecting more of the available relevant dose-response information and alternative risk characterizations. (7) Risk should be characterized in terms of the net effect of a dose on health rather than a dose's effect on a single factor affecting health - for example, risk would be better expressed in terms of mortality from all causes combined rather than a specific type of fatal disease.

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Quantitative Risk Assessment of Human Salmonellosis and Listeriosis Related to the Consumption of Raw Milk in Italy

Journal of Food Protection ◽

10.4315/0362-028x.jfp-14-171 ◽

2015 ◽

Vol 78 (1) ◽

pp. 13-21 ◽

Cited By ~ 13

Author(s):

FEDERICA GIACOMETTI ◽

PAOLO BONILAURI ◽

SABRINA ALBONETTI ◽

SIMONETTA AMATISTE ◽

NORMA ARRIGONI ◽

...

Keyword(s):

Risk Assessment ◽

Consumer Behavior ◽

Dose Response ◽

Raw Milk ◽

Storage Conditions ◽

Entire Population ◽

Quantitative Risk Assessment ◽

Public Health Perspective ◽

Vending Machines ◽

Milk Storage

Two quantitative risk assessment (RA) models were developed to describe the risk of salmonellosis and listeriosis linked to consumption of raw milk sold in vending machines in Italy. Exposure assessment considered the official microbiological records monitoring raw milk samples from vending machines performed by the regional veterinary authorities from 2008 to 2011, microbial growth during storage, destruction experiments, consumption frequency of raw milk, serving size, and consumption preference. Two separate RA models were developed: one for the consumption of boiled milk and the other for the consumption of raw milk. The RA models predicted no human listeriosis cases per year either in the best or worst storage conditions and with or without boiling raw milk, whereas the annual estimated cases of salmonellosis depend on the dose-response relationships used in the model, the milk storage conditions, and consumer behavior in relation to boiling raw milk or not. For example, the estimated salmonellosis cases ranged from no expected cases, assuming that the entire population boiled milk before consumption, to a maximum of 980,128 cases, assuming that the entire population drank raw milk without boiling, in the worst milk storage conditions, and with the lowest dose-response model. The findings of this study clearly show how consumer behavior could affect the probability and number of salmonellosis cases and in general, the risk of illness. Hence, the proposed RA models emphasize yet again that boiling milk before drinking is a simple yet effective tool to protect consumers against the risk of illness inherent in the consumption of raw milk. The models may also offer risk managers a useful tool to identify or implement appropriate measures to control the risk of acquiring foodborne pathogens. Quantification of the risks associated with raw milk consumption is necessary from a public health perspective.

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