The First Report: Toxicity Testing for Assessment of Environmental Agents

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En provenance du cours de Johns Hopkins University

Toxicology 21: Scientific Applications

10 notes

Johns Hopkins University

Toxicology 21: Scientific Applications

10 notes

This course familiarizes students with the novel concepts being used to revamp regulatory toxicology in response to a breakthrough National Research Council Report “Toxicity Testing in the 21st Century: A Vision and a Strategy.” We present the latest developments in the field of toxicology—the shift from animal testing toward human relevant, high content, high-throughput integrative testing strategies. Active programs from EPA, NIH, and the global scientific community illustrate the dynamics of safety sciences.

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Module 1

This model will give you a broad introduction to the Toxicology 21st century (Tox21c) field and familiarize you with the main document, which summarize the main ideas and principles of Tox21c.

Historical Perspective17:43

The First Report: Toxicity Testing for Assessment of Environmental Agents11:30

The Second Report: Toxicity Testing in the 21st Century: A Vision and A Strategy Vision and Its Components22:08

Rencontrer les enseignants

Lena Smirnova
Research Associate
Center for Alternatives to Animal Testing
Thomas Hartung
Professor
Environmental Health and Engineering

Welcome back to the lecture on the NRC report,

Toxicity Testing in the 21st Century, a Vision, and a Strategy.

In section B of the lecture, we're going to talk about the first report,

Toxicity Testing for Assessment of Environmental Agents.

The book, Toxicity Testing for Assessment of Environmental Agents,

can be downloaded through the National Academy Press, and

I've put the website for this on the lecture page.

In addition, a published summary of the reports of the Tox 21 Committee,

can be found at the reference by Krewski et al, shown below.

The first report had eight chapters which are listed below.

It dealt with a general introduction, and

then a chapter on current animal and in vitro toxicity testing.

A chapter on human data, that can be applied to toxicity testing and

risk decisions that are made on the basis of the results of the testing,

and human exposure data, and human outcome data.

Because many of these compounds or chemicals are already in commercial use.

A chapter on strategies for toxicity testing,

another on the use of data in human health risk assessment.

One that begins to address new approaches, and

one that begins to address alternative approaches and emerging technologies.

So in the rest of this section,

I'm just going to talk about a few highlights from this first report.

In this chart, I show the main federal agencies that are responsible for

toxic chemical regulation.

I also showed this chart in the Public Health Toxicology course.

And so as we know, that there's the FDA, the EPA, OSHA,

The Occupational Safety and Health Administration, CPSC,

the Consumer Product Safety Commission, and the Department of Transportation.

And they all work under a legislation passed by congress, and

this is listed below in the table.

And the chemicals that these agencies are responsible for,

are shown in the column on the right, so FDA covers drugs and food additives.

EPA has a very broad mandate to cover air and

water pollutants, contaminated sites, environmental estrogens and

endocrine disrupters, pesticides, and other toxic substances.

OSHA is focused on occupational exposures, Consumer Product and

Safety Commission is focused on consumer products.

And the Department of Transportation is mainly concerned with the shipping

of hazardous materials.

And each of these has certain types of testing requirements,

or guidelines at least, for companies that are manufacturing and

marketing various chemicals that end up in commerce and in the environment.

The exposure-response continuum that underlies the current paradigm for

toxicity testing, is shown in this chart.

So exposure results in a tissue dose,

a tissue dose is really the internal dose to the organism.

And what we're concerned about, if you remember from Public Health Toxicology,

is what is the biologically effective dose?

That is, what is the component of the internal dose

that actually interacts with a critical cellular target?

And then what are the early responses and the late responses

that ultimately may cause a pathology or an adverse health effect?

So this paradigm focuses on adverse health outcomes as endpoints,

and these are referred to as apical endpoints for assessing risk.

That is, what are the adverse effects, what is the pathology, there aren't

intermediate endpoints that are used at this point in the risk assessment process.

Although, mechanistic data can be used by the risk assessors to impact their final

risk assessment, the endpoint is, at this point, always some apical response.

So this slide lists a number of in vivo toxicity tests.

Over the past several decades, scientists have developed consensus testing protocols

to minimize variance and bias, reduce false positives,

which are type one errors, and false negatives, which are type two errors.

This current system relies on a complex system of whole animal-based strategies or

hazard identification and dose-response assessment.

And the main tests include, acute toxicity tests, subchronic, or

repeat-dose toxicity tests, and chronic toxicity and carcinogenicity tests.

If you remember from Public Health Toxicology, the last two,

subchronic and chronic, toxicity tests,

the data that they provide can be used in the risk assessment process.

Testing for specific endpoints may also be required, for example, developmental and

reproductive toxicity is assessed by 1-generation or 2-generation tests.

There are also tests for neurotoxicity, immunotoxicity, genotoxicity and

carcinogenicity.

Here we are looking at data needed for

risk assessment versus the data that's generated from the specific tests.

For example, the cancer guidelines require direct evidence of cancer in animals or

humans, to classify a chemical as a human carcinogen.

But when it's not available a cancer risk is not able to be estimated.

So, what we need is a system for

indirect evidence, such as structure activity and mechanistic data that

is able to guide the assessment if we don't have data from humans or animals.

With regard to mutagenic or an unknown mechanism for carcinogens, we assume that

each individual in the population has the same level of risk when they are exposed.

Current testing strategies do not address potential human variability and

susceptibility.

So we need testing strategies that could actually begin to look at what is

the potential human variability in the population, or sensitivity to

adverse outcomes upon exposure to a given environmental agents.

With regard to mode of action evaluations and pharmacokinetic, or

toxicokinetic modeling, this is typically done ad hoc.

And this really begins to get at, upon exposure,

how is a chemical distributed in the body?

And what are the amounts of the chemical that actually reach the organs and

tissues within the body?

This can be modeled through pharmacokinetic and toxicokinetic models.

And as I indicate, it's just not routinely done,

and the data for this type of modeling may not always be available.

Major limitations of the current testing strategies,

are that low dose extrapolation from high dose testing is a real concern.

Now why do we do high dose testing?

Well there's a need for

sufficient statistical power to observe high dose effects using relatively small

numbers of test animals in relatively short periods of time.

It's impossible to go to very low doses because the percent of the animals that

would be showing an effect, would become very small.

So you would need huge numbers of animals, and from a resource point of view, and

a tactical point of view, this is just not able to be done.

In addition, there's the inability to test a wide range of

doses using animals in toxicity testing.

Typically there's a control that's unexposed, and

then at the most, three doses of the test compound are used.

The other issue is the animal to human extrapolation.

Many times we're not sure if the animals that are used in testing, typically

rats and mice, but also dogs, and in some cases primates, especially for drugs.

When they're used, we're not sure in all instances, or in most instances,

that the chemical is being metabolized and

handled the same way in the animal as it might be in a human.

And furthermore, there's a real difficulty of assessing mixtures, and

as you can probably appreciate, we are exposed to mixtures.

There are many chemicals in our environment,

both in the personal care products we use, and the food we eat, and in the general

environment walking down the street with exhaust fumes and particulates, etc.

And the ability of being able to test for

the toxicity caused by mixtures of these agents at very low levels just

doesn't exist using the current toxicity-testing methods.

So, there are a number of proposals to improve toxicity-testing strategies,

of the committee felt that the system has reached a turning point,

it's reached saturation.

There's not much else that can be done to increase its output its accuracy

in detecting chemicals, that at very low doses, through which humans

are normally exposed, as to whether or not they're having any adverse health effects.

So, the regulatory agencies, as I've mentioned previously, have responded to

the scientific advances and challenges, by altering the tests or adding tests.

And it's really been a patchwork approach that is not really fully satisfactory.

So there are four objectives of toxicity-testing, one is depth.

So down at the bottom, you can see that we want a detailed mechanistic

understanding and dose information for human health risk assessment.

And we want to be able to have this for a number of compounds in great depth.

So we really understand what kinds of effects these chemicals may be having

on cells and tissues and organ systems.

Up at the top, you can see we want breadth,

we want the broadest coverage of chemicals and end points and life stages.

We don't only get exposed as adults,

we get exposed throughout our life beginning in utero.

So the developing fetus and embryo is exposed through the mother, and

then from birth on, we're exposed to a variety of chemicals.

And sure, the chemicals that we're exposed to may change over time, but

exposure to environmental chemicals is continuous.

There are also animal welfare issues, we want to cause the least suffering possible

and use the fewest number of animals.

This requires that we have well designed toxicity-tests

when we need to use animals.

And that we would only use animals when absolutely necessary,

because we would have alternative testing strategies that could be used first.

And we need endpoints, such that we can detect an adverse effect in the animal

before the animal begins to suffer from that adverse effect.

And we also need conservation, we need the lowest cost and the least time,

we have to minimize the expenditure of resources.

So there can be disagreements as to which of the four of these is most important.

For instance, with the endocrine disruptor screening program,

the primary objective was breadth.

Wanted to be able to test many different environmental chemicals as to whether or

not they could have adverse health effects mediated through

altering the hormonal systems in our bodies.

That was a primary driving factor, and

some of the protocols that were developed were very animal intensive for instance.

And so there was less attention to that objective of toxicity-testings, so

there's this conflict between these four objectives.

So this concludes the second section of this lecture.

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