Page 61 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

28 SECTION | I General

VetBooks.ir of the exposure levels originally selected for studies. To may not always incorporate a SF or UF of 10 for human
variability. The exposure duration for TLVs is based on a
state the obvious, observations can only be made at the
40-h work week and, thus, the results of animal studies
exposure levels studied. For example, if the exposure
levels studied did not extend to a sufficiently low level, will be normalized to 40 h per week.
the lowest level might produce an effect thereby preclud- The Agency for Toxic Substances and Disease
ing observation of a NOAEL. Alternatively, the study Registry (ATSDR) develops Minimal Risk Levels
might be designed with three exposure levels separated by (MRLs) using a similar methodology. A MRL is an
a factor of 10 with the lowest exposure level identified as estimate of the daily human exposure to hazardous
a NOAEL and the next higher exposure level identified as substance that is likely to be without appreciable risk
producing some modest adverse effects and, thus, identi- of adverse noncancer effects over a specified duration
fied as the LOAEL. In retrospect, in such a study it is not of exposure. For example, MRLs are derived for acute
known whether the “true” LOAEL might have been a fac- (1 14 days), intermediate (14 365 days), and chronic
tor of three or five above the NOAEL since these levels (365 days and longer) exposure durations. The MRLs are
were not investigated. intended to serveasascreeningtooltohelppublic
Another consideration is the nature of the effects iden- health professionals decide to look more closely at
tified at the NOAEL. Was there evidence of enzyme particular exposure situations. The ATSDR has prepared
induction or hyperplasia, hypertrophy, or atrophy with no toxicological profiles on many chemicals including their
evidence of a change in organ weight? Likewise, at the MRLs. More than 200 profiles are available on line
LOAEL were hyperplasia, hypertrophy, or atrophy pres- (ATSDR, 2006).
ent resulting in modest or substantial changes in organ The NIOSH has in the past developed Recommended
and body weight? Were histological changes observed Exposure Levels (RELs). RELs are set at levels such that
that were reversible? Were the changes sufficiently pro- virtually all persons in the working population (with the
found that the level would be identified as a functional possible exception of hypersensitive individuals) would
effect level? These questions serve to emphasize the experience no adverse effects. In late 2016, the NIOSH
extent to which professional judgment is involved in issued an updated cancer policy (NIOSH, 2016). This pol-
interpreting the results of all toxicological investigations. icy stated that NIOSH will no longer use the term REL
For noncancer effects a reference dose (RfD) for oral for occupational carcinogens. Instead, NIOSH will pro-
intake or a inhalation reference concentration (RfC) for vide a Risk Management Limit for a Carcinogen, which is
airborne materials is calculated using the NOAEL or to be identified as an RML-CA. NIOSH made this change
LOAEL as a starting point (Jarabek et al., 1990; Jarabek, to acknowledge there is no known safe level for exposure
1994). An RfD or RfC may be defined as an estimate to carcinogens and that an RML-CA is a reasonable start-
(with uncertainty spanning perhaps an order of magni- ing point for controlling exposures. The new policy states
tude) of a continuous oral or inhalation exposure to the the RML-CA will be set for occupational carcinogens at
human population (including sensitive subgroups) that is the concentration corresponding to the 95% lower confi-
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likely to be without appreciable risk of deleterious non- dence limit of the 1 in 10,000 (10 ) risk estimate.
cancer effects during a lifetime. The RfD and RfC values NIOSH intends to set RML-CA values for agents classi-
are developed from the experimentally determined fied by IARC, EPA, or the NTP as possible, probable, or
NOAEL or LOAEL values as shown in Fig. 1.10 human carcinogens. The Occupational Safety and Health
(Jarabek, 1994) and normalized to continuous exposure. Administration sets Permissible Exposure Levels (PELs)
For a more complete description of the process, the reader based on consideration of the NIOSH RELs. Presumably
is referred to a book chapter by McClellan et al. (2006). in the future it will set PELs based on the RML-CA value.
The EPA maintains an Integrated Risk Information It is important to recognize the OSHA values are legally
System that includes comprehensive summaries of the enforceable limits unlike the NIOSH RELs or RML-CA
toxicological information available on specific chemicals values, which are guidance.
including RfD and RfC values and estimates of cancer- The International Programme on Chemical Safety
causing potency. These profiles are available on line (IPCS) prepares authoritative reviews on the environmen-
(EPA/IRIS, 2011). tal health impact of various chemicals. The reports are
A somewhat similar approach for noncancer effects available on line (IPCS, 2011). The exposure limiting
has been used by the ACGIH to develop TLVs (ACGIH, values developed by the IPCS are guidance values and
2011). A TLV is defined as airborne concentrations of not legally enforceable limits. The United States makes
substances that represent conditions under which it is extensive use of legal enforceable exposure limits. Many
believed that nearly all workers may be repeatedly other countries emphasize the use of guidance values.
exposed day after day without adverse health effects. This distinction is important when comparing standards
Since the ACGIH TLVs apply to healthy workers they versus guidance originating from different countries.