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LAB
to LABEL
People
in general have a poor concept of what it takes to bring an agricultural
product to the farm. Many have misconceptions concerning toxicological
and environmental testing, and government regulations and requirements.
Only about one in 20,000 compounds pass testing from synthesis
to field use. It undergoes some 120 separate toxicological and
environmental tests, ensuring that the compound poses no health
or environmental concerns when used properly. Product development,
testing and approval by the EPA takes from eight to 10 years and
costs over $50 million (1990). This also leaves only about seven
to nine years on the patent for the developer to recoup the costs.
Because
of the importance for people to understand this process, this
is the first part of a multi-part article on the general scheme
for taking a compound out of a test tube to the crop. The article
is based on my decade-long experience as a researcher in a chemical
company and a brochure called "from Lab to Label" published
by the American Crop Protection Association.
Phase
I. Screening (Discovery)
Primary
Screening
Small
quantities, as little as an ounce, of a compound is synthesized.
The compound may be a derivative of another compound, an analog,
or a foray into a new chemical sequence, or a by-product of a
methodology used for something else, commonly a fermentation by-product.
(The latter is the reason why most large ag-chemical manufacturers
are closely related to a pharmaceutical manufacturer, such as
Bayer.) In a large ag-chemical company 10 to 20 thousand compounds
are made each year; exact numbers are kept confidential.
These
compounds are tested routinely in special laboratory and greenhouse
tests developed by the company's researchers. They are tested
in these mini-screens for activity. The protocols for these tests
are kept under trade secrets and change according to market development
and interest.
After
this initial screening, 100 to 500 of the 10-20,000 show some
interesting activity warranting further testing in the greenhouse
or insectary, etc. At this point, the first toxicological tests
kick in. The most important and immediate test is the Ames mutagenicity
test. This laboratory test on bacteria looks to see if the compound
can alter DNA, normally by base substitution, and results are
back in a few days. If it does, it's finished and will never leave
the lab. The only testing permitted is by company researchers
under highly protective conditions in the lab. This limited testing
may be done by the researcher for various reasons, usually to
define structure-activity relationships and look for non-mutagenic
analogs.
If
the compound passes this test, it will undergo an eye irritation
test with a rabbit. This is a mild test and used as a guide for
applicators. If the compounds might be tested other than locally
at the research and development center, it must go through both
oral and dermal toxicity tests on mice. This will determine the
compounds LD50 or what is the dose for 50% mouse mortality when
the compound is ingested or in skin contact. If the LD50s are
acceptable, it is cleared for shipping in sealed packages.
Secondary
Screen
About
100 to 500 compound per year are retested in the laboratory and
greenhouse. These tests are designed to determine active rates
and application timings, and determine the target pest and crop.
Compound may be tested several times before going to the field
for testing. Compounds that look promising are re-synthesized
in slightly large quantities, 1 to 5 ounces.
Tertiary
Screen
This
is the first field screening of compounds. Of the compounds tested
in the secondary screen, 10 to 60 compounds will undergo small
scale field tests. These tests are conducted initially on company
research farms and are conducted in small plots. Application timing
and method, rates, and some structure/activity tests are conducted.
Analogs of active compounds are synthesized and tested in the
secondary screens for activity and patent purposes. All of these
analogs are also tested in the mutagenicity test and active ones
are further put through the eye irritation, dermal toxicity and
oral toxicity tests. From the initial field test, a few compounds,
less than 10, are sent for testing by a few University researchers
around the country in small plot evaluations to confirm the company's
research and to determine activity in a wider range of situation.
At
this time, the selected compounds undergo formulation testing.
Formulation testing looks at different carriers and physical properties
of the compounds. University researchers get test compounds in
a preliminary formulation, usually a liquid flowable (LF), emulsifiable
concentrate (EC) or wettable powder (WP). This is quite different
than the form in the primary and secondary screens in which the
compound is unformulated and tested in a solvent such as acetone.
At
the same time, environmental impact testing begins on compounds
going into tertiary screening. The compound's persistence in different
soils and breakdown by soil microbes are key tests. Its volatilization
and solar effects are measured. How it is metabolized by both
the target crops and pests are determined using radio labeled
tagging. The method of uptake, for instance root or foliar, and
percent penetration and translocation are determined.
Toxicological
testing is expanded to determine speed and amount mice excrete
the compound, urine and feces. The metabolic breakdown of the
compound in mice is determined, and all metabolic products are
identified. These are called the "7-day toxicology studies"
and a problem here, such as the formation of a dangerous by-product
in the mouse, would eliminate the compound and possibly the whole
chemistry from further testing.
In
summary Phase II testing involves field efficacy trials, preliminary
formulation studies, environmental persistence determinations,
plant and/or pest metabolism, and rodent excretion and metabolism.
Of
the 10-20,000 compounds that are screened each year (Phase I),
only one to six go into Phase
II Development.
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