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Toxicity Testing in Animals

Toxicity Testing in Animals

Toxicity tests in animals are grounded on two main assumptions: first, the effects observed in laboratory animals can be extrapolated to humans, especially when adjusted for body surface area; second, high-dose exposure in animals is essential to identify potential human hazards from lower doses. This is based on the quantal dose-response concept, which faces the challenge of extrapolating results from relatively few test animals to much larger human populations. For example, a 0.01% incidence...

Toxic Reactions: Overview

Toxic Reactions: Overview

When toxic substances penetrate the human body, they disseminate to various tissues, undergoing metabolic changes. This process yields reactive metabolites that may covalently bind with specific target molecules, resulting in toxicity.
Toxicity falls into two primary categories: local and systemic.
Local toxicity appears at the exposure site, such as protein denaturation caused by caustic substances.
In contrast, systemic toxicity requires the toxic agent's absorption and distribution,...

Drug Toxicity: Dose-Dependent Reactions

Drug Toxicity: Dose-Dependent Reactions

Drug toxicities can be stratified into pharmacological, pathological, or genotoxic based on their mechanisms. The incidence and severity of these toxicities generally increase with the drug's concentration in the body and exposure time.Pharmacological toxicity is evident when the therapeutic effects of drugs overshoot into adverse reactions in a predictable, dose-dependent manner. Central nervous system (CNS) depression from barbiturates is a classic example, with effects escalating from...

Mutagenicity and Carcinogenicity

Mutagenicity and Carcinogenicity

Mutagenicity and carcinogenicity refer to the ability of drugs to cause genetic defects and induce cancer, respectively. The International Agency for Research on Cancer (IARC) classifies agents into four groups based on their carcinogenic potential. Group 1 agents are known human carcinogens; group 2A agents are probably carcinogenic to humans; group 3 agents lack data to support their role in carcinogenesis; and group 4 includes agents for which data support that they are not likely to be...

Drug Toxicity: Overview

Drug Toxicity: Overview

Drug toxicity quantifies the harm a compound causes to an organism, varying by dose and potentially impacting whole systems or specific organs like the liver. Toxic reactions may arise from venomous insect or spider bites, with effects ranging from mild symptoms to severe outcomes such as brain damage or death. Common forms of acute poisoning include ethanol intoxication and overdose of pain or fever medications, with substances like GHB and heroin being particularly lethal at doses close to...

Toxicokinetics: Overview

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Studies that assess how a drug is absorbed, distributed, metabolized, and excreted (ADME) at toxic doses are termed toxicokinetics. Understanding toxicokinetics helps predict adverse drug reactions (ADRs) and manage toxicity in humans.Toxicokinetics differs from pharmacokinetics mainly in the dose levels studied, with toxicokinetics focusing on higher toxic doses. The kinetics at these levels can be non-linear due to altered physiological processes. Toxicodynamics examines the relationship...

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Advanced 3D Liver Models for In vitro Genotoxicity Testing Following Long-Term Nanomaterial Exposure

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Rethinking guideline toxicity testing.

Shakil Ahmed Saghir¹

¹Smithers Avanza Toxicology Services, 11B Firstfield Road, Gaithersburg, MD 20878, United States.

Regulatory Toxicology and Pharmacology : RTP

|May 19, 2015

Summary

Updating risk assessment guidelines for plant protection products (PPPs) is crucial. Determining systemic dose, especially the kinetically-derived maximum dose (KMD), in animals improves hazard assessment and reduces animal testing.

Keywords:

Agrochemical Environmental chemical Industrial chemicals KMD Kinetically-derived maximum dose Non-pharmaceuticals Plant protection products Systemic dose

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Area of Science:

Toxicology
Risk Assessment
Environmental Science

Background:

Current guidelines for plant protection product (PPP) risk assessment are outdated, not reflecting advancements in toxicology and exposure sciences.
Existing methods rely on maximum tolerated dose (MTD), often at doses with limited human relevance, necessitating further mode-of-action (MoA) studies.

Purpose of the Study:

To propose an improved tiered approach for PPP risk assessment emphasizing systemic dose determination in test animals.
To advocate for toxicity studies at kinetically linear doses or near the point of nonlinearity (KMD) for more relevant hazard assessment.

Main Methods:

Focus on determining the systemic dose of parent compounds and/or metabolites in test animals.
Identifying the kinetically-derived maximum dose (KMD) as a critical parameter.
Utilizing core study animals to determine systemic dose and assess linearity.

Main Results:

Systemic dose, particularly KMD, provides a more sensitive indicator of potential toxicity than MTD.
Nonlinearity in systemic dose indicates toxic effects not relevant to human exposure scenarios.
Determining systemic dose enhances understanding of PPPs' mode of action and potential human exposure risks.

Conclusions:

Implementing systemic dose determination, especially KMD, in animal studies significantly improves the accuracy of PPP hazard assessment.
This approach enhances the toxicological understanding of PPPs and reduces the need for additional animal testing by avoiding unnecessary MoA studies.