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Observational studies in humans provide the basis for much of what is known about the toxicokinetics and toxicity of lead and are summarized in this section.  References to, and summaries of,  the human data are made in the endpoint summaries of individual toxicological endpoints.

Additional information

Toxicokinetics

Lead is most easily taken up into the body through inhalation or ingestion – dermal uptake makes a negligible contribution to systemic lead levels. Once taken up into the body, lead is not metabolized. However, lead will distribute to a variety of tissue compartments such as blood, bone and soft tissues. The half-life of lead in the body varies as a function of body compartment. Lead in blood has a half life of 30 – 45 days – measurement of lead in blood thus provides an integrated assessment of average lead exposure (via all routes) over the preceding month. Lead is retained far longer in bones. Depending upon bone type, the retention time of lead can vary between 8 and 30 years. Such lead can both serve as a source of endogenous lead exposure and as a cumulative index of exposure over a time frame of years. Lead excretion is primary via urinary and biliary excretion routes.

Representative uptake rates for lead in adults and children via different exposure routes are presented below. These representative uptake rates can be applied to calculate the uptake of lead from individual exposure sources, but are put forward with the caveat that the kinetics of lead uptake can be curvilinear in nature and subject to modification by a number of variables. The uptake estimates given are thus representative values that are only applicable to relatively low exposure levels yielding blood lead levels < 10 – 15 µg/dL.

Representative lead uptake rates

Intake route

Adults

Children

Oral (food)

10%

50%

Oral (soil)

6%

30%

Dermal

<0.01%

<0.01%

Air (deep lung deposition)

100%

100%

Air (upper airway deposition)*

Variable

NA

*Upper airway deposition is expected for many occupational aerosols and uptake will thus vary as a function of pulmonary deposition patterns and the extent of translocation to the gastrointestinal tract where GI uptake kinetics will predominate. Non-linearity as a function of exposure level imparts additional variability into upper airway uptake estimates. Given that upper airway deposition is expected primarily in the occupational setting, upper airway deposition is Not Applicable (NA) to children.

The uptake rates listed above are essentially the consensus uptake rates adopted by national and international risk assessment agencies. Various modifiers of uptake rate exist. Moreover, alternate uptake rates would be assumed if more sophisticated exposure assessment models were being used. For example, PBPK modelling obtains best fit data through the application of alternate gastrointestinal uptake values. For the very young a higher uptake rate of 58% is applied, but then declines as a linear function of age until adult lead uptake rates are attained at age 8. A baseline adult gastrointestinal uptake rate of 8% is further assumed, a value lower than the 10% default that might otherwise be assumed since deposition and subsequent remobilisation of bone lead contributes to lead in blood.

For the practical purpose of rapidly relating exposure to potential blood lead levels, it can be useful to evaluate potential impacts of lead exposure using “slope factor” relationships. Use of slope factor relationships permit rapid conversion of estimated lead intake rates into incremental changes in blood lead. Representative slope factor relationships are presented below. The relationships are only valid for the exposure ranges at which they were derived. Impacts from ambient air, lead in food or lead in soil are thus applicable when baseline blood lead levels are 10 – 15 µg/dL or lower. Occupational air slope factors are relevant to occupational (e.g. > 30 µg/dL) blood lead. There is strong non-linearity in the toxicokinetics of lead that limits of range of exposure over which a given slope factor estimate is valid. A dermal uptake slope factor is not presented inasmuch as this exposure route has not been deemed significant by most toxicologists and no efforts have been made to derive slope factors in the scientific literature. Higher or lower slope factors may be observed as a function of critical exposure variables that alter duration of exposure, the particle size distribution of lead (especially for air) or that modify the bioavailability of ingested lead. Curvilinear toxicokinetics will also tend to depress these slope factors at higher levels of exposure. The large slope factor difference between occupational and ambient air lead exposures is thus a function of eight hours of occupational exposure compared to 24 hr exposure to ambient air, non-linear toxicokinetics at elevated occupational blood lead levels, and predominantly upper airway deposition in the occupational setting that results in low GI uptake kinetics compared to the high rates of lead uptake that would result from alveolar deposition of lead in ambient air. Finally, slope factor relationships cannot be used in isolation to determine the impact of lead upon blood lead – they represent regression coefficients that define a best-fit line with a y intercept (blood lead) that is not zero. For example, slope factors for the impact of lead in air upon children do not consider indirect deposition pathways for exposure. Similarly, occupational air lead slope factors are only applicable when due consideration is given to the exposure baseline that results from uptake through other intake pathways. Finally, these estimates are applicable only for estimating the impacts of chronic exposure.

Representative slope factors

Media

Adults*

Children*

Blood lead range where slope factor is valid

Ambient air (1 µg/m3)

1.64 µg/dL

1.92 µg/dL

< 10 – 15 µg/dL

Occupational air (1 µg/m3)

0.02 – 0.08 µg/dL

NA

> 30 µg/dL

Lead in Food (1 µg intake/d)

0.05 µg/dL

0.16 µg/dL

< 10 – 15 µg/dL

Lead in Soil and Dust (1 µg intake/d)

0.03 µg/dL

0.10 µg/dL

< 10 – 15 µg/dL

*Blood lead increase from indicated incremental increase in exposure to the medium in question and must be interpreted considering baseline exposure levels from other intake pathways. Occupational lead exposure is Not Applicable (NA) to children and no occupational air slope factor estimate is provided.

Although lead uptake rates and slope factor relationships can be provided, the actual amount of lead to which individuals are exposed can be difficult to estimate. Under most circumstances, adult blood lead levels in the general population will be dictated by lead intake from food and beverages. Air lead levels can be significant contributors around local sources and/or in situations where leaded gasoline is in use. Soil and dust ingestion makes a limited contribution to adult blood lead levels, but this contribution is generally secondary in magnitude to that from other sources.

In contrast, soil and dust ingestion are usually presumed to constitute the primary exposure pathway for children. Although acceptable blood lead levels can be exceeded due to lead in air, water or food, it is most often lead in soil or dust that is the principal determinant of paediatric lead exposure. In the vicinity of point sources, contributions of air lead to blood lead will result from direct inhalation and indirect deposition pathways (ingestion of lead in dust deposition). The actual level of soil and dust ingestion that is assumed in risk characterisation will vary as a function of lifestyle circumstances. Alternate assumptions can be made and instances where such altered assumptions are warranted should be noted.

Estimated environmental lead levels can be used as input parameters for computer-based exposure assessment models and predictions made of resulting blood lead levels. Some exposure assessment models offer the dual advantage of both translating environmental lead levels into predicted blood lead levels and estimating the variability in blood lead that would be expected in the population. These predictions can then be contrasted with observational blood lead data and an assessment made as to whether or not there is concordance between the two. Computer-based exposure assessment models also automatically adjust for non-linearity in the toxicokinetics of lead uptake and excretion. Point estimates of uptake (or slope factor estimates) are applicable for specific levels of expected exposure and can over- or under-estimate exposure if applied to individuals with blood lead baselines different from those upon which uptake estimates are based.

In instances of chronic lead exposure affecting children, impacts upon blood lead can be assessed using the IEUBK model developed by U.S., EPA (Win32 version 1.0). Initial model runs are made using worst case default assumptions for exposure to estimate blood lead levels, or increases in blood lead, that might be associated with a lead exposure scenario. Since the model is limited to predicting the blood lead levels of children, it cannot be applied for evaluation of some of the exposure scenarios that must be considered. The O’Flaherty PBPK model (ver. 1.0) is instead applied to estimate blood lead elevations that may occur in adults. Where feasible, the results of models are further compared with slope factor estimates of blood lead impact.

Although the application of computer-based exposure assessment models confers multiple technical advantages, caution must be exercised in applying such models. Existing lead exposure assessment models were principally developed in the United States and reflect exposure situations that characterise US lifestyles and activities. As such, critical model assumptions need not accurately reflect exposure conditions relevant to the EU. Modelling is most likely to be problematic for predicting the exposure of children to soil and dust in urban environments where little soil is present. Exposure assessment models predict a combined soil and dust intake level and further presume that concentrations of lead in household dust are determined by the lead content of nearby soils. Urban EU environments may present minimal opportunity for exposure to bare soil and an overestimate of soil ingestion may result. Furthermore, if little soil is present, the concentration of lead in house dust may be determined by factors (e.g. atmospheric deposition rates) that existing lead exposure assessment models are not designed to predict. Exposure assessment models from the United States have principally been validated in rural exposure environments in the vicinity of local point sources and will overestimate lead exposure in urban environments. Fortunately, the models are designed to be flexible and permit modification of key input parameters. Modification of default assumptions for exposure and uptake should, however, be undertaken with caution using either site specific data or in instances where blood lead monitoring data are available to validate model predictions.

Observations of Toxicity in Humans

NOAEL’s developed for critical health endpoints resulting from repeated dose toxicity are all based upon the concentration of lead in blood, an internal exposure biomarker that integrates all routes through which lead might be expected to enter the body. NOAEL’s for different health endpoints thus related to micrograms of lead per decilitre of blood (µg/dL) as opposed to a quantity of lead that is ingested or inhaled. All health endpoints of concern are manifestations of systemic effects and are independent of exposure route. There are no local effects that would dictate development of an exposure route specific NOAEL indexed to external dose. Descriptors for acute toxicity testing conducted in animals are given in route specific dose descriptors. However, in the absence of either local effects or acute toxicity, these data are not used for DNEL derivation and it is presumed that DNEL’s for chronic exposure will be more than adequately protective against acute toxicity. Systemic NOAEL’s are further put forward for separate sensitive subpopulations. Thus there are NOAEL’s for the developing foetus, children, woman of reproductive capacity as well as a overall DNEL for individuals who do not fall into one of the sensitive subpopulation groups.

The NOAEL’s were identified from multiple (in some case in excess of 100) scientific studies of human populations. This has permitted detailed evaluation of issues such as age, gender, ethnicity, intensity of exposure and duration of exposure that can be sources of uncertainty in effects assessment. Given that extrapolations are not made from animal studies and that specific NOAEL’s have been derived for susceptible subpopulations there is diminished need to correct for inter-species variability with Assessment Factors. Separate NOAEL’s have been developed for sensitive subpopulations and accommodate intra-species variability that might otherwise require the use of an Assessment factor.

NOAEL’s derived for different health endpoints are shown in the following table. Those NOAEL’s that are the lowest for a given subpopulation are shown in bold text. From this table it can be seen that NOAEL’s have been proposed for the most sensitive subsets of the population and define blood lead levels protective against subtle effects. Whereas there are NOAEL’s indexed to endpoints that constitute a material impairment of health, the NOAEL’s derived in this assessment protect against preclinical effects that precede material health impairment.

NOAEL’s and proposed blood lead levels for different exposed populations

Health effects endpoint

NOAEL

Exposed population

Renal system effects

 

60 μg/dL

25 µg/dL

Adults

Child

Haematological effects

 

50 μg/dL

40 µg/dL

Adults

Child

Reproductive effects (male)

45 μg/dL

Male Adults

Nervous system effects (adult)

40 μg/dL

Adults

Reproductive effects (female)

30 μg/dL

Women of child-bearing capacity

Nervous system effects (foetal developmental effects) during pregnancy

10 μg/dL

Pregnant women/women of child-bearing capacity

Nervous system effects (child)

10 μg/dL

Individual Child

Nervous system effects (child)

5 µg/dL

Population Based Child Limit

 

Note that the human data indicated carcinogenicity, genotoxicity and cardiovascular endpoints were not appropriate endpoints for use in risk assessment. The most sensitive NOAEL’s in adults protect against effects known to be reversible if exposure is reduced.

 The dose response for lead toxicity is steep and increases the precision with which NOAEL’s can be identified. For example, although sub-clinical manifestations of neurotoxicity may be manifested in adults in the range of 40 – 50μg/dL, significant cognitive impairment would be expected to result from a doubling of blood lead.