Download How to deal with safety assessment tolerance and toxicological

How to deal with safety assessment
tolerance and toxicological aspects
Alberto Mantovani
Vice-chair of EFSA FEEDAP Panel
Director of
Food and Veterinary Toxicology Unit
Istituto Superiore di Sanità, Roma
[email protected]
EFSA FEEDAP Panel
additives and products or substances used in
animal feed.
(www.efsa.europa.eu/en/feedap/feedapscdocs.htm)
A large and heterogenous group of compounds
Comprising natural compounds, xenobiotics
microorganism-derived substances
- different usages/exposure patterns of
animals/humans/environment
- different biological properties
=
- different critical points for risk assessment
and
Risk assessment what does it mean ?
To integrate characterization of hazards and
exposure
so to assess “whole-cycle” safety based on
intended conditions of use
for the animal (target species/category for which
use is intended)
the consumer of products of animal origin
the user/worker
the environment
= safe for consumer does not mean (necessarily)
safe
Let’s go stepwise throughout these aspects
Product characteristics should be defined, including
Safety relevant information
- Undesirable substances (“source impurities”) (toxic
elements, dioxins, mycotoxins, infectious or toxigenic
bacteria. Presence and maximum traces under EC
regulation)
-process impurities (e.g., residual solvents), especially if
limited information or structural alerts (e.g., genotoxicity)
(care about product specification)
- Stability of, e.g., vitamins: if not guaranteed, risk of
deficiency may occur in target species
Dusting potential, respirable fraction: Key parameter to
user exposure assessment
TOLERANCE IN TARGET SPECIES,
“Tolerance = a limited evaluation of the short-term toxicity
for the target animals
Means that a full toxicological package for the target
species is out of scope
Does NOT mean that safety of use can be demonstrated
using just zootechnical parameters
Check gross (and histo-, if indications) pathology, blood
haematology and chemistry,
focus on appropriate markers for a given substance (e.g.,
gastric lesions in pigs for benzoic acid 2005, 2007)
Derive margin of safety = test at use level and at
overdosing (up to 10-fold) for sufficient time (see
FEEDAP Guidance on tolerance/efficacy 2011)
CONSUMER SAFETY
Hazard identification (what does it do ?)
Toxicological studies for xenobiotics (e.g., coccidiostats)
The usual full-package, but mind:
Keep updated with new developments e.g.
- OECD guidelines (e.g. new “extended one-generation”
would replace two-generation study using less animals)
-EFSA Scientific Committee (2011) has defined that in vivo
genotoxicity is a self-standing effect, not just a “predictor
of carcinogenicity” (thus, a negative carcinogenicity study
does not rule out a positive genotoxicity assay)
CONSUMER SAFETY
Hazard identification (what does it do ?) (cont)
For enzymes, probiotics, specific forms of nutrients
a limited testing package -90-day rodent + in vitro/in vivo
genotoxicity- to show any specific/unexpected toxicological
effect of the compound (e.g., organic forms of trace
elements)
For nutrients in general a Upper Tolerable Level (“the
nutrient ADI”) has been defined by the EU SCF (till 2003)
or by the EFSA Panel NDA (2003 onward), based –in most
cases- on human studies.
In a few cases (e.g., vitamin A, 2009) the FEEDAP has
searched and used guidance values more updated than the
UL.
HAZARD CHARACTERIZATION: the use of dose-response
data
FEEDAP has been an early user of Benchmark Dose (EFSA
Scientific Committee 2009)
(derive threshold value from a dose-response and 95%
confidence limits for critical effect)
Ractopamine (2009): beta-agonist, proposed as growth
promoter in fattening pigs and beef
No firm basis to derive a NOAEL for pharmacological
(cardiovascular) adverse effects from human data
This is the case to apply Benchmark dose
a “safe level” could not be established, as to exclude the critical
changes (e.g., + 20 % in heart rate), the lower confidence limit
of the benchmark dose would be 0 mg.
Thus, with the current database a ADI could not be
CONSUMER SAFETY: EXPOSURE
What can tell us experimental studies
Kinetics
What are the target tissues/products for residues ?
What is the residue marker (biologically significant and
representative – in a given ratio- of total residues ?)
For xenobiotics (like coccidiostats) are the same
metabolites being present in laboratory animals and in
target species ?
Means: are relevant metabolites being tested in
toxicological studies ?
Re-assessment of nicarbazin (2010)
Toxicological assessment of nicarbazin is relevant to
target species safety and user exposure
But in tissue most residues are represented by the 4,4
dinitrocarbaniline (DNC) moiety of nicarbazine, which,
thus is the marker residue and the one relevant to
consumer exposure
DNC has a much lower toxicity than nicarbazine
/ADI 0,77 mg/kg bw vs. 0.05 mg/kg bw, respectively)
CONSUMER EXPOSURE
Residue studies (basis for consumer's exposure)
Take care: assess residues at maximum recommended dose
for realistic intake time
(at least three sampling points after withdrawal)
in all edible tissues (meat, fat, liver, kidney, fish flesh) and
products (milk and eggs) of major species (if many species)
or of target species as appropriate.
(Feed additives: mass continuous exposure, long
withdrawal time is undesirable)
Deposition studies for nutritional
(specific forms of vitamins, trace elements)
Target: measure any increase of the substance related to
the specific form (e.g., Se-yeast, 2011) to be tested
Animals fed the highest intended level of use AND with
total feed content compliant with the maximum EU
allowable content (if this exists: Se, Cu, Vitamin A; if not,
it should be compatible with good animal husbandry
practices: Vitamin E or water-soluble vitamins)
Mind: measure the background level in feed
N.B. No residue studies are required for
enzymes/probiotics, technological additives that do not
remain in feeds, substances not absorbed
CONSUMER SAFETY
Risk characterization
Xenobiotics: derive ADI and (if required) Maximum
Residue Limits compatible with ADI
Nutrients: if UL exists considers exposure from tissue
deposition in supplemented animals + Background intake
(EFSA data)
If no UL and unsolved concerns for consumers safety (e.g.,
Manganese): assess whether the use of the feed additive
does increase the consumers exposure over the
background in any significant way (e.g., Mn Mintrex, 2008,
2009, 2010)
MIND: Specific forms of nutrients (in particular organic
forms of trace elements) have higher bioavailability = tissue
Risk characterization requires comparison between
ADI/UL and consumer exposure
(guidance on consumer safety, 2012)
Established approach using default daily adult human
consumption figures for relevant foods of animal origin
(used for veterinary drug residues by EMA)
it assumes: only adults/only chronic/all consumers
-Alternative approach: default values from EFSA
Comprehensive European Food Consumption Database:
high intake (95th percentile) of consumers only for each
food item
-More realistic, differentiates between chronic and acute
intake as well as between adults and children (e.g., hemp
as feed material, 2011; Se-yeast, 2011)
USER SAFETY: A relevant issue that has always to be
taken into account (FEEDAP guidance, 2012)
Apparently a rather straight (even though tiresome) data
set
Toxicity testing on “site effects” Dermal//eye irritancy.
Skin sensitisation (no appropriate test for respiratory
sensitization)
Human data if available
Acute inhalation toxicity: repeated dose assessment if
significant systemic exposure may occur
Exposure: Particle size distribution and the content of the
active substance(sin dust following the measurement of the
dusting potential.
USER SAFETY:
A model for calculating daily exposure of workers in a
premixture plant to the active substance is provided by
Guidance.
What outcome ?
Precautionary measures may be proposed to reduce or
eliminate exposure.
Use of personal protective devices should only be regarded
as a measure of last resort to protect against any residual
risk once other control measures are in place, e.g.,
reformulation of the product.
Can we recommend restriction on a feed additive solely for
user safety ? YES
Cobalt salt and user safety (2009) a general background opinion
- Co supplementation to diets for ruminants, horses and rabbits
should be maintained as it meets animal physiology
- Co has remarkable toxicity including carcinogenicity
- However (considering uncertainties) non-B12 Co in animal
tissues/products + background intake will provide less than
0.05 mg/day vs. a UL of 0.6 mg/day
- Co compounds (dichloride and sulfate) are skin and
respiratory sensitizers and carcinogenic by inhalatory route.
No detailed user exposure for authorised compounds in feeds,
but user exposure cannot be avoided.
- (i) restrict the use of Co to ruminants, horses and rabbits, (ii)
limit feed supplementation to < 0.3 mg, (iii) reduce the max. Co
in feed from 2 to 1 mg/kg for all species except fish. No negative
consequences on animal health and production are expected.
ENVIRONMENTAL SAFETY: EXPOSURE-DRIVEN
(Guidance 2008) Natural compounds: show whether the
use in feed and presence in animal excreta may change
background environmental concentrations (unlikely)
Otherwise, stepwise, multi-tier assessment:
Phase I (additives not intended for farm animals or
providing an insignificant predicted environmental
concentration-PEC)
Phase IIA: PEC + Predicted No Effect Concentration
(PNEC) values for ground and water compartment based
on a limited set of fate and effect (acute) studies
Phase IIB: detailed ecotoxicological studies in the
environmental compartment(s) in which Phase IIA studies
indicate possible concern
ENVIRONMENTAL SAFETY
Additives of potential concern include
Coccidiostats (highly active and highly excreted in active
form; however, low persistence/bioaccumulation: e.g.,
nicarbazin, 2010)
Some trace elements like Zinc or Copper: recent opinion
on Zn sulphate monohydrate (2012) rules out any impact
from use in aquaculture or for agricultural soil
compartment, but
potential environmental concern related to drainage and
run-off of zinc to surface water. Most vulnerable for these
processes are acid sandy soils
Additional data are required
SOME (hopefully not too) RANDOM SUGGESTIONS
for making steps forward; traslational research (from
bench to risk analysis)
-Impact on feed additives (including probiotics/enzymes)
on the nutritional quality of animal feeds and human foods
- Adverse interactions between feed additives and between
feed additives and feed materials
- Refine consumer exposure (consumer’s niches)
- bioavailability and safety of different nutrient forms (e,g,
folic acid vs folates) for target species and consumers
-- Risk-benefit of “risk reducing” additives (e.g., intended
to lower nitrogen output or bind contaminants)
-. Refine environmental exposure and effects
SOME REFERENCES FROM US
Mantovani A, Maranghi F, Purificato I, Macrì A. (2006)
Assessment of feed additives and contaminants: an essential
component of food safety. Ann Ist Super Sanita 42, 427-32.
Mantovani A, Frazzoli C, La Rocca C. (2009) Risk assessment
of endocrine-active compounds in feeds. Veterinary Journal
182, 392-401.
Mantovani A, Frazzoli C, Cubadda F. (2010) Organic forms of
trace elements as feed additives: assessment of risks and
benefits for farm animals and consumers. Pure and Applied
Chemistry. 82, 393-407.
That’s all Folks…