**General Question 1**

**What are the radiation exposure levels (rate, quality, amount) that
result in CNS injury?**

-   Endpoints

-   Surrogate endpoints

-   Latency

-   Models (Is risk established?)

-   Age, status of CNS

Dr. Rabin presented the following recommendations of the subgroup that
were discussed and edited by all participants.

######## Exposures

*Protons*

For investigating proton effects the strategy should be to simulate the
background exposure from galactic cosmic rays and other sources. Low
dose rates should be generated using multiple small fractions consistent
with the operation of accelerator facilities. The dose range should be
from about 0.5 to 4 Gray. These time dose factors should include the
dose and fractionation schedule: for example, the number of fractions
per day, the total number of days, and ultimately, the total number of
fractions. The samples should be analyzed at various times to map the
time response of the exposures. It is presumed that large-scale
experiments will be required for statistical significance.

NASA should recommend a reference field for normalization and cross
comparison of experimental exposures. Standard exposure paradigms are
desirable in general and defined protocols should be established.

*Heavy Ions*

For investigating heavy ion effects the strategy should be to examine
the energy and LET dependence (dose composition) of the particles and to
target specific regions in the brain. Particles of different residual
ranges will span different penetration depths in the CNS and the
microlesion concept should be revisited. The effect of dose rate should
be examined on selected end points. The RBE vs. LET dependence of
endpoints should be determined where possible.

[Endpoints]{.underline}

CNS damage and repair should be examined at the cellular through system
levels. In anticipating exposure requirements it should be noted that
exposure levels 5 to 10 times higher than for system level endpoints
have been required for some previously demonstrated effects at the
cellular level.

Acute effect studies should include examination of performance deficits
and must take into account the prior history of the subjects (such as
head trauma). Latent effect studies should address the increased risk
for the occurrence and early onset of neurodegeneration. Such processes
would be influenced by synaptic and neural plasticity.

[Models]{.underline}

In selecting models for study it is critical that a multidisciplinary
approach be used. The approach should include morphology,
neurochemistry, behavioral modification, including sensory and motor,
cognitive and affect (aggressive, passive, and other attitude changes),
sensory, motor and cognitive functioning. It should examine multiple
targets in the CNS and determine if effects of radiation exposure on the
CNS are primary or secondary to systemic effects. At the cellular level
neuronal stem cells and cells from genetically modified animals should
be used to test mechanisms. Explants and tissue slices provide
intermediate levels of organization with representative anatomical
organization. At the system level studies should be designed informed by
data from human subjects and there should be a general examination of
established rodent models for behavior, and neurodegenerative conditions
such as Parkinson's disease.

*A critical requirement that was identified is to obtain baseline and
post-exposure performance data for sensory, behavioral modification,
including sensory and motor, cognitive and affect (aggressive, passive,
and other attitude changes), motor and cognitive functioning in the
relevant human population. This might be accomplished by examination of
brain-irradiated patients treated for malignant and non-malignant
disease (e.g., arterio-venous malformations) before and after one dose
fraction of about 2 Gray.*